Total submissions: 52
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Dasa | RCV000148905 | SCV007594658 | pathogenic | Li-Fraumeni syndrome | 2025-04-28 | criteria provided, single submitter | clinical testing | NM_000546.6(TP53):c.844C>T (p.Arg282Trp) introduces an arginine to tryptophan substitution at a mutational hotspot. Functional studies demonstrate loss of transactivation activity (PMID: 12826609, 30224644). This variant has been recurrently observed in individuals with Li-Fraumeni syndrome and related cancers. Based on the available data, this variant is classified as Pathogenic. |
| Genetics Laboratory, |
RCV000148905 | SCV007593441 | pathogenic | Li-Fraumeni syndrome | 2026-03-10 | criteria provided, single submitter | clinical testing | PS4_moderate, PP3_supporting, PS3_strong, PM1_moderate, PS2_strong |
| Institute of Human Genetics, |
RCV000148905 | SCV007494687 | pathogenic | Li-Fraumeni syndrome | 2026-02-18 | criteria provided, single submitter | clinical testing | This variant has been identified by standard clinical testing. |
| Institute for Genomic Medicine |
RCV000148905 | SCV007449412 | pathogenic | Li-Fraumeni syndrome | 2025-02-11 | criteria provided, single submitter | clinical testing | This variant has been reported to occur de novo in an affected individual in the literature with parental identity confirmed (ACMG/AMP: PS2_Moderate; PMIDs:22672556, 16206219). Well-established functional studies have demonstrated this variant to have a damaging effect on protein function or splicing (ACMG/AMP: PS3; PMIDs:12826609, 30224644). This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4_VeryStrong; PMIDs:8425176, 25925845, 1565144, 11370630, 10864200, 8402598, 1349175, 17567834, 25293557, 25896519, 1565143, 30709381, 35974385, 29237527, 18511570). This variant is located in a mutational hot spot and/or critical and well-established functional domain (ACMG/AMP: PM1). This variant is absent from or present at an exceedingly low frequency in gnomAD, a large-scale control population database (ACMG/AMP: PM2_Supporting). This variant is predicted to alter protein function or structure, or disrupt splicing by multiple in silico tools (ACMG/AMP: PP3_Moderate). |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000236400 | SCV007111890 | pathogenic | not provided | 2025-01-23 | criteria provided, single submitter | clinical testing | The TP53 c.844C>T (p.Arg282Trp) variant has been reported in the published literature in numerous individuals with Li-Fraumeni syndrome and Li-Fraumeni syndrome-related cancers (PMIDs: 35974385 (2022), 35831225 (2022), 33932062 (2021), 31081129 (2019), 30709381 (2019), 25925845 (2015), 25584008 (2015), 22672556 (2012), 21305319 (2011), 16206219 (2006), 11370630 (2001), 10864200 (2000), 8425176 (1993). Functional analysis in cell culture and mice indicates that this variant results in aberrant function, leading to invasive cell growth and accelerated tumorigenesis (PMID: 24857548 (2014)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. |
| Institute for Genomic Medicine |
RCV006253490 | SCV007105732 | tier i - strong | Diffuse glioma, H3 G34 mutant | 2023-09-26 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse glioma, H3 G34 mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644, 29979965). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 28966033, 24705251, 26482474, 34519829, 35195909). |
| Institute for Genomic Medicine |
RCV006253485 | SCV007105598 | tier i - strong | Melanoma | 2025-04-04 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in melanoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644, 29979965). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 22817889, 26091043, 28467829, 36098958, 35121978, 33230298). |
| Institute for Genomic Medicine |
RCV006253486 | SCV007105559 | tier ii - potential | Low grade glioma | 2024-09-06 | criteria provided, single submitter | clinical testing | Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in low grade glioma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644). 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMIDs: 23583981, 11523567, 8834542, 32619305, 30051528, 12484572). |
| Institute for Genomic Medicine |
RCV006253491 | SCV007105348 | tier ii - potential | Juvenile type testicular granulosa cell tumor | 2023-06-21 | criteria provided, single submitter | clinical testing | Variant has Tier II (potential) clinical significance as a diagnostic inclusion criterion in juvenile type testicular granulosa cell tumor, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant. 3) Diagnostic significance based on multiple small studies (Evidence Level C; PMID: 18669439). |
| Institute for Genomic Medicine |
RCV006253484 | SCV007105228 | tier i - strong | Rhabdomyosarcoma | 2024-06-07 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant. 3) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24436047, 34166060, 24332040, 25768946, 26138366). |
| Institute for Genomic Medicine |
RCV006253487 | SCV007105150 | tier i - strong | Astrocytoma IDH-mutant | 2024-04-11 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in Astrocytoma IDH-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Information in the literature supports potential biologic effect of variant. 3) Diagnostic for a specific tumor type/classification according to professional guidelines (Evidence Level A; PMIDs: 22869205, 23104868, 26061751). |
| Institute for Genomic Medicine |
RCV006253492 | SCV007105028 | tier i - strong | Signet ring cell carcinoma | 2024-02-20 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in signet ring cell carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant. 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMID: 35618879). |
| Institute for Genomic Medicine |
RCV006253489 | SCV007105006 | tier i - strong | Medulloblastoma WNT activated | 2024-02-14 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in medulloblastoma WNT activated, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644, 29979965). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 21163964, 28726821, 22832583, 22820256). |
| Institute for Genomic Medicine |
RCV006253488 | SCV007104479 | tier i - strong | Diffuse midline glioma, H3 K27M-mutant | 2023-02-16 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in diffuse midline glioma, H3 K27M-mutant, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 12826609, 30224644, 29979965). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24705251, 28966033, 22661320, 34796414, 33433639). |
| All of Us Research Program, |
RCV000148905 | SCV005425720 | pathogenic | Li-Fraumeni syndrome | 2024-05-14 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with tryptophan at codon 282 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes reduced transactivation activity, dominant negative effect, and loss of function in human cell proliferation and growth suppression assays (PMID: 12826609, 15958617, 21343334, 29979965, 30224644). This variant has been reported in many individuals affected with breast cancer, Li-Fraumeni syndrome, and Li-Fraumeni-like syndrome meeting Chompret criteria, including several de novo cases (PMID: 8402598, 8425176, 11370630, 1565143, 16206219, 19468865, 21305319, 21761402, 22672556, 25584008, 25619955, 28975465, 30709381). This variant has been identified in 1/251410 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
| Molecular Diagnostics Laboratory, |
RCV000210145 | SCV005407751 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-04-19 | criteria provided, single submitter | clinical testing | c.844C>T, located in exon 8 of the TP53 gene, is predicted to result in the substitution of Arginine by Tryptophan at codon 282, p.(Arg282Trp). This variant is localted in a well-known mutational hotspot (PM1). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.542) (PP3_Moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). Moreover, the variant also shows loss of function (RFS=0.1645) in an assay based on in vitro growth assays in H1299 human cells (PMID: 29979965). This variant has been reported in 8 Chompret families with a TP53-related phenotype, which awards 4.5 point to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 1565143, 19012332, 19468865, 21761402, 25584008, 26014290) (PS4). In addition, the variant co-segregates in the two families from our clinical cohort of patients (4 meiosis, PP1). This variant has been reported in the ClinVar database (1x likely benign, 24x likely pathogenic, 25x pathogenic) and in the LOVD database (1x likely pathogenic, 3x pathogenic, 1x NA). Based on currently available information, c.844C>T is classified as a pathogenic variant according to ClinGen-TP53 Guidelines version v1.4. |
| Center for Genomic Medicine, |
RCV004668718 | SCV005094389 | oncogenic | Neoplasm | 2025-03-04 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV004566738 | SCV005054335 | pathogenic | Adrenocortical carcinoma, hereditary | 2024-02-14 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000148905 | SCV004848861 | pathogenic | Li-Fraumeni syndrome | 2022-11-03 | criteria provided, single submitter | clinical testing | The p.Arg282Trp variant in TP53 has been reported in at least 4 individuals with features of Li-Fraumeni syndrome (Wasseman 2015 PMID: 25584008, Wu 2011 PMID: 21305319, Melhem-Bertrandt 2012 PMID: 21761402,Toguchida 1992 PMID: 1565143) and in ClinVar (Variation ID 12364). It has also been identified in 1/68022 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg282Trp variant is located in the DNA binding domain of the TP53 protein and in vitro functional assays support impact on protein function with loss of transactivation capacity and dominant negative effect, affecting several p53 isoforms (IARC TP53 database, Monti 2011 PMID: 21343334, Zerdoumi 2017 PMID: 28472496, Kato 2003 PMID: 12826609). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP criteria applied: PM1, PP3, PS3, PS4, PM2_Supporting. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000148905 | SCV004241252 | pathogenic | Li-Fraumeni syndrome | 2023-12-18 | criteria provided, single submitter | clinical testing | Variant summary: TP53 c.844C>T (p.Arg282Trp) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251810 control chromosomes. c.844C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome. Experimental studies have shown the variant to have a damaging effect on protein function. The following publications have been ascertained in the context of this evaluation (PMID: 23246812, 11370630, 27895058, 16818505, 11782540, 22915647, 21059199, 26230955, 1349175, 21519010, 20407015, 27463065, 22672556, 1565144, 30327374, 17606709, 21343334, 26585234, 25952993, 27276561, 22186996, 27680515, 1565143, 27959731, 21305319, 24857548). 21 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Myriad Genetics, |
RCV000144670 | SCV004017907 | pathogenic | Li-Fraumeni syndrome 1 | 2023-04-12 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 1565144, 8425176, 16206219, 22672556, 33407742, 29581140]. Functional studies indicate this variant impacts protein function [PMID: 1631137, 17015838, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. |
| KCCC/NGS Laboratory, |
RCV000144670 | SCV004015238 | pathogenic | Li-Fraumeni syndrome 1 | 2023-07-07 | criteria provided, single submitter | clinical testing | This sequence change replaces Arginine with Tryptophan at codon 282 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein which interacts with multiple proteins. This variant is present in population databases at a very low frequency ( rs28934574, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 25584008, 21305319, 21761402, 1565143). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. In addition, experimental studies have shown that this variant affects TP53 transactivation activity at variable levels. The mutation database ClinVar contains entries for this variant (Variation ID:12364). Therefore, this variant is considered as pathogenic. |
| Laboratory of Medical Genetics Unit, |
RCV003315223 | SCV004012928 | likely pathogenic | Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype | 2019-02-12 | criteria provided, single submitter | research | |
| Institute of Human Genetics, |
RCV000144670 | SCV002757862 | pathogenic | Li-Fraumeni syndrome 1 | 2022-11-07 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV000144670 | SCV002583007 | likely pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV000210145 | SCV002582345 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| MGZ Medical Genetics Center | RCV000144670 | SCV002581144 | pathogenic | Li-Fraumeni syndrome 1 | 2022-08-08 | criteria provided, single submitter | clinical testing | |
| Sema4, |
RCV000210145 | SCV002532713 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-10-31 | criteria provided, single submitter | curation | |
| Neuberg Centre For Genomic Medicine, |
RCV000144670 | SCV002073337 | pathogenic | Li-Fraumeni syndrome 1 | criteria provided, single submitter | clinical testing | The missense variant p.R282W in TP53 (NM_000546.6) has been reported in multiple affected patients (Mannan AU et al; Siraj AK et al). Functional studies suggest a damaging effect (Zerdoumi Y et al). The variant has been submitted to ClinVar as Pathogenic. The p.R282W variant is observed in 1/1,13,728 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R282W missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 282 of TP53 is conserved in all mammalian species. The nucleotide c.844 in TP53 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. | |
| Genetic Services Laboratory, |
RCV000236400 | SCV002069228 | pathogenic | not provided | 2018-08-08 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.844C>T, in exon 8 that results in an amino acid change, p.Arg282Trp. The p.Arg282Trp change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg282Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the EXAC database with a low population frequency of 0.002% (dbSNP rs28934574). The p.Arg282Trp pathogenic sequence change has previously been described in multiple unrelated individuals with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome, and has been observed in the de novo state in at least two affected individuals (Malkin et al., 1992; Bougeard et al., 2001; Pinto et al., 2009; Wu et al., 2011; Kast et al., 2012; Melhem-Bertrandt et al., 2012; Wasserman et al., 2015). Functional studies have provided evidence that the p.Arg282Trp sequence change has a dominant negative effect and leads to significantly reduced TP53 transcriptional activity in response to DNA damage (Zerdoumi et al., 2017). |
| Baylor Genetics | RCV000144670 | SCV002030224 | pathogenic | Li-Fraumeni syndrome 1 | 2021-01-06 | criteria provided, single submitter | clinical testing | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Institute of Biochemistry, |
RCV001270278 | SCV001450497 | pathogenic | Colorectal cancer | criteria provided, single submitter | case-control | ||
| Institute of Biochemistry, |
RCV000441472 | SCV001450496 | pathogenic | Squamous cell carcinoma of the head and neck | criteria provided, single submitter | case-control | ||
| St. |
RCV000722016 | SCV000853189 | pathogenic | Astrocytoma, anaplastic; Pleomorphic xanthoastrocytoma | 2016-11-04 | criteria provided, single submitter | clinical testing | This is a missense alteration in which a C is replaced by a T at coding nucleotide 844 and is predicted to change an Arginine to a Tryptophan at amino acid codon 282. Classification criteria: PS3, PM1, PM2, PP3, PP5. |
| Mendelics | RCV000148905 | SCV000839109 | pathogenic | Li-Fraumeni syndrome | 2018-07-02 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000210145 | SCV000821787 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-01-01 | criteria provided, single submitter | clinical testing | This sequence change replaces Arginine with Tryptophan at codon 282 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein which interacts with multiple proteins. There is a large physiochemical difference between arginine and tryptophan (Grantham Score 101).This variant is present in population databases at a very low frequency ( rs28934574, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 25584008, 21305319, 21761402, 1565143). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. In addition, experimental studies have shown that this variant affects TP53 transactivation activity at variable levels. In summary, this is a rare sequence change that is expected to affect the TP53 protein and cause disease.The mutation database Clinvar contains entries for this variant (Variation ID:12364). |
| Color Diagnostics, |
RCV000210145 | SCV000691656 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-03-20 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with tryptophan at codon 282 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant is deficient for transcriptional transactivation activity, causes a dominant negative effect, and exhibits loss of function in human cell proliferation and growth suppression assays (PMID: 12826609, 15958617, 21343334, 29979965, 30224644). This variant has been reported in many individuals affected with breast cancer, Li-Fraumeni syndrome, and Li-Fraumeni-like syndrome meeting Chompret criteria, including several de novo cases (PMID: 8402598, 8425176, 11370630, 1565143, 16206219, 19468865, 21305319, 21761402, 22672556, 25584008, 25619955, 28975465, 30709381). This variant has been identified in 1/251410 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
| Center for Personalized Medicine, |
RCV000144670 | SCV000680092 | pathogenic | Li-Fraumeni syndrome 1 | 2018-02-04 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000210145 | SCV000581079 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-07-05 | criteria provided, single submitter | clinical testing | The p.R282W pathogenic mutation (also known as c.844C>T), located in coding exon 7 of the TP53 gene, results from a C to T substitution at nucleotide position 844. The arginine at codon 282 is replaced by tryptophan, an amino acid with dissimilar properties. This pathogenic mutation has been reported in multiple individuals or families with Li-Fraumeni Syndrome (LFS) or LFS-like syndrome (Toguchida J et al. N. Eng. J. Med. 1992 May;326(20):1301-8; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Kast K et al. BMC Cancer. 2012 Jun;12:217; Mannan AU et al. J. Hum. Genet. 2016 Jun;61:515-22; Siraj AK et al. Hum. Genet. 2017 11;136:1431-1444). In an analysis of data from the p53 germline mutation database, mutations at position R282 were shown to have an association with early onset bone cancers (Xu J et al. Sci. Rep. 2014;4:4223). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on the available evidence, this alteration is classified as a pathogenic mutation. |
| Illumina Laboratory Services, |
RCV000144670 | SCV000407070 | pathogenic | Li-Fraumeni syndrome 1 | 2017-04-27 | criteria provided, single submitter | clinical testing | The TP53 c.844C>T (p.Arg282Trp) variant is listed as a common somatic and germline variant in the IARC TP53 variant database (Arcand et al. 2015; Wassermann et al. 2015). Across a selection of the available literature the TP53 c.844C>T (p.Arg282Trp) variant has been identified in at least nine individuals with different types of cancer, all in a heterozygous state (Toguchida et al. 1992; Malkin et al. 1992; Audrezet et al. 1996; Prochazkova et al. 2009; Pinto et al. 2009; Melhem-Bertrandt et al. 2012; Sokolenko et al. 2015). The p.Arg282Trp variant has also been found in a heterozygous state in at least two asymptomatic family members. The variant was absent from 200 control individuals and is reported at a frequency of 0.0002 in the European American population of the Exome Sequencing Project. This frequency is based on two alleles in a region of good coverage so the variant is presumed to be rare. Functional studies using the p.Arg282Trp variant protein document that the variant destabilizes the protein, increases aggregation and alters signalling to increase cellular invasion (Zhang et al. 2016). Based on the collective evidence, the p.Arg282Trp variant is classified as pathogenic for Li-Fraumeni syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Gene |
RCV000236400 | SCV000292698 | pathogenic | not provided | 2021-05-21 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato et al., 2003; Scian et al., 2004; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32658383, 32475984, 31980526, 31105275, 32098966, 31537539, 31081129, 31159747, 30840781, 31016814, 30720243, 30709381, 28472496, 25186627, 28975465, 29555771, 29752822, 28861920, 29581140, 15280671, 29979965, 29315962, 29506128, 29300620, 29237527, 27882657, 28534505, 27683180, 28091804, 28369373, 27680515, 28387325, 28527674, 27077130, 28397142, 25925845, 8402598, 19468865, 18669439, 1349175, 8425176, 10864200, 21761402, 22672556, 27501770, 27714481, 27619989, 26911350, 25385265, 26878390, 26014290, 25619955, 15077194, 21343334, 21305319, 25637381, 24651015, 24573247, 14583457, 16206219, 1565144, 25584008, 19012332, 11370630, 21059199, 1565143, 12517413, 21445056, 12917626, 12826609, 16861262, 1631137, 17606709) |
| University of Washington Department of Laboratory Medicine, |
RCV000210145 | SCV000266136 | pathogenic | Hereditary cancer-predisposing syndrome | 2015-11-20 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000148905 | SCV000253852 | pathogenic | Li-Fraumeni syndrome | 2026-01-02 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 282 of the TP53 protein (p.Arg282Trp). This variant is present in population databases (rs28934574, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome (PMID: 1565143, 1565144, 11370630, 21305319, 21761402, 25584008). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12364). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. |
| Department of Clinical Biochemistry, |
RCV001270278 | SCV006076894 | tier ii - potential | Colorectal cancer | 2024-10-10 | no assertion criteria provided | research | Missense |
| Clinical Genetics and Genomics, |
RCV004797589 | SCV005419166 | pathogenic | TP53-related disorder | 2024-10-01 | no assertion criteria provided | clinical testing | |
| BRCAlab, |
RCV000210145 | SCV002589036 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-08-26 | no assertion criteria provided | clinical testing | |
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785546 | SCV000924118 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research | |
| Counsyl | RCV000144670 | SCV000785099 | pathogenic | Li-Fraumeni syndrome 1 | 2017-04-18 | no assertion criteria provided | clinical testing | This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. |
| Mayo Clinic Laboratories, |
RCV000236400 | SCV000692065 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| CSER _CC_NCGL, |
RCV000148905 | SCV000190651 | likely benign | Li-Fraumeni syndrome | 2014-06-01 | no assertion criteria provided | research | |
| Pathway Genomics | RCV000144670 | SCV000190002 | pathogenic | Li-Fraumeni syndrome 1 | 2014-07-24 | no assertion criteria provided | clinical testing | |
| OMIM | RCV000013161 | SCV000033408 | pathogenic | Li-fraumeni-like syndrome | 1995-01-01 | no assertion criteria provided | literature only |