Total submissions: 31
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Dasa | RCV000420734 | SCV007599509 | pathogenic | not provided | 2026-03-02 | criteria provided, single submitter | clinical testing | NM_000546.6(TP53):c.638G>A (p.Arg213Gln) is a missense variant that results in the substitution of arginine with glutamine. The affected residue or protein region has prior evidence supporting clinical relevance. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 18208484; PMID: 16494995; PMID: 17541742; PMID: 20522432; PMID: 12826609). This variant has been recurrently observed in individuals with related phenotype (PMID: 18208484; PMID: 16494995; PMID: 17541742; PMID: 20522432; PMID: 12826609). Multiple computational predictions support a deleterious effect on the gene or gene product. The variant is present at low frequency in population datasets. Based on the available data, this variant is classified as pathogenic. |
| Institute for Genomic Medicine |
RCV000123099 | SCV007449436 | pathogenic | Li-Fraumeni syndrome | 2024-03-08 | criteria provided, single submitter | clinical testing | Well-established functional studies have demonstrated this variant to have a damaging effect on protein function or splicing (ACMG/AMP: PS3; PMIDs:12826609, 30224644, 28369373, 29979965). This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4_Moderate; PMIDs:28369373, 32019277, 25925845, 20522432, 18208484, 16494995). 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). |
| Center for Genomic Medicine, |
RCV006273527 | SCV007129867 | oncogenic | Neoplasm | 2025-12-29 | criteria provided, single submitter | clinical testing | |
| Institute for Genomic Medicine |
RCV006253811 | SCV007105605 | tier i - strong | Embryonal rhabdomyosarcoma | 2025-05-19 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, 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 (PMID: 10871862). 4) 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 |
RCV006253810 | SCV007104732 | tier i - strong | Adrenal cortex carcinoma | 2024-01-15 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in adrenal cortex 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 (PMIDs: 30224644, 12826609). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 25743702, 17289876, 25490274, 11454518, 27165744, 24747642, 33534120). |
| Molecular Diagnostics Laboratory, |
RCV000130072 | SCV005407759 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-08-16 | criteria provided, single submitter | clinical testing | c.638G>A, located in exon 6 of the TP53 gene, is predicted to result in the substitution of Arginine by Glutamine at codon 213, p.(Arg213Gln). This variant is found in 1/236928 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C35; BayesDel: 0.5) (PP3). 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). At least, this variant has been reported in 3 individuals affected with a TP53-related phenotype, which awards 2 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 25293557, 16736287) (PS4_moderate). It has been reported in ClinVar (13x as pathogenic, 22x as likely pathogenic, 1x NA), LOVD (3x as pathogenic, 1x as NA) and CancerHotspots (25 somatic observations, PM1). Based on the currently available information, c.638G>A is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4. |
| Neuberg Centre For Genomic Medicine, |
RCV000144664 | SCV005329582 | pathogenic | Li-Fraumeni syndrome 1 | 2023-05-20 | criteria provided, single submitter | clinical testing | The observed missense variant c.638G>A (p.Arg213Gln) in the TP53 gene has been reported previously in mulitple individual(s) with Li-Fraumeni syndrome (LFS) or LFS-associated malignancies. Experimental studies have shown that this missense change affects TP53 function (Silva AG, et al., 2012; Monti P, et al., 2007). Different amino acid changes such as p.Arg213Pro and p.Arg213Leu have been reported previously as pathogenic and likely pathogenic at the same position (Dockhorn-Dworniczak B, et al., 1996; Veldore VH, et al., 2015). This variant is reported with the allele frequency 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic by multiple submitters. The amino acid Arginine at position 213 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. |
| All of Us Research Program, |
RCV000123099 | SCV004823777 | pathogenic | Li-Fraumeni syndrome | 2024-01-22 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glutamine at codon 213 in the DNA binding domain 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 results in the loss of DNA binding and transactivation activity of TP53 protein (PMID: 7885831, 10871862, 12826609, 16736287, 24384472). This variant has been reported in an individual affected with Li-Fraumeni syndrome (Color internal data) and in individuals meeting the Chompret criteria of Li-Fraumeni syndrome (PMID: 17541742, 23259501). In a large pedigree that meets the Birch criteria of Li-Fraumeni-like syndrome, this variant has been shown to segregate with late-onset breast cancer, ovarian cancer, colorectal cancer, renal cell cancer, melanoma, mesothelioma and lung cancer in 12 family members (PMID: 16736287). This variant has been observed in individuals not meeting Li-Fraumeni syndrome diagnostic criteria but affected with breast cancer (PMID: 17541742, 20522432, 31119730, 32019277; Color internal data) and sarcoma (PMID: 19468865). An analysis of IARC's TP53 germline variant dataset has shown this variant to exhibit reduced penetrance (PMID: 29076966). This variant has been identified in 1/251462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. This variant may display reduced penetrance relative to typical pathogenic TP53 variants. Medical management should be considered based on the individual's personal and family history. |
| Baylor Genetics | RCV003460862 | SCV004206242 | pathogenic | Adrenocortical carcinoma, hereditary | 2023-08-22 | criteria provided, single submitter | clinical testing | |
| Institute of Human Genetics, |
RCV000144664 | SCV003925607 | pathogenic | Li-Fraumeni syndrome 1 | 2023-07-26 | criteria provided, single submitter | clinical testing | Criteria applied: PS3,PS4,PM5_STR,PM2_SUP |
| St. |
RCV000144664 | SCV003843119 | pathogenic | Li-Fraumeni syndrome 1 | 2022-10-17 | criteria provided, single submitter | clinical testing | The TP53 c.638G>A (p.Arg213Gln) missense change has a maximum subpopulation frequency of 0.0046% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in multiple individuals with Li-Fraumeni syndrome (LFS) or LFS-associated cancers and has been found to segregate with disease in families (PMID: 16494995, 16736287, 17541742, 18208484, 19468865, 20522432, 25293557, 28369373). Computational evidence supports a deleterious effect of this variant on protein function (Align GVGD = C35, BayesDel = 0.5033). Transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID 12826609, 30224644). This variant is a somatic hotspot variant in tumors according to the Cancer Hotspots database (cancerhotspots.org). In summary, this variant meets criteria to be classified as pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000123099 | SCV003800820 | pathogenic | Li-Fraumeni syndrome | 2023-01-30 | criteria provided, single submitter | clinical testing | Variant summary: TP53 c.638G>A (p.Arg213Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four 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 251462 control chromosomes (gnomAD). c.638G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and associated cancers, and has been shown to segregate with disease within families (e.g. Ruijs_2006, Arcand_2008, Sheng_2020). These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown that this missense change significantly affects the functional activity of the TP53 protein, diminishing its DNA-binding and transcriptional transactivation activities in yeast-based assays, and has been functionally classified as a partial deficiency (PD) or severe deficiency (SD) allele (PMID: 16736287, 21343334, 12826609, 17606709). Ten ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Genome- |
RCV000144664 | SCV002583142 | pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV000130072 | SCV002582482 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| CHEO Genetics Diagnostic Laboratory, |
RCV001798386 | SCV002042828 | pathogenic | Breast and/or ovarian cancer | 2019-08-09 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000420734 | SCV001469324 | pathogenic | not provided | 2024-02-23 | criteria provided, single submitter | clinical testing | The TP53 c.638G>A (p.Arg213Gln) variant has been reported in the published literature in individuals with late onset breast, ovarian, and choroid plexus carcinomas, as well as in affected individuals with Li-Fraumeni syndrome (PMIDs: 32019277 (2020), 31119730 (2020), 30720243 (2019), 26270727 (2015), 24728327 (2014), 23259501 (2012), 16736287 (2006)). It has also been observed as early onset in an affected individual with gray zone lymphoma (PMID: 30299350 (2019)). A yeast based functional study of this variant showed a lack of transcriptional activity (PMID: 1676287 (2006)). 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. |
| Clinical Genetics and Genomics, |
RCV000420734 | SCV001449717 | pathogenic | not provided | 2018-03-27 | criteria provided, single submitter | clinical testing | |
| Human Genome Sequencing Center Clinical Lab, |
RCV000123099 | SCV001434920 | pathogenic | Li-Fraumeni syndrome | 2019-02-21 | criteria provided, single submitter | clinical testing | The c.638G>A (p.Arg213Gln) variant in the TP53 gene has been reported in multiple families affected with Li-Fraumeni (LFS) or Li-Fraumeni-like (LFL) syndromes (PMID 16736287, 16494995, 19468865, 20522432) and is extremely rare in general population databases. Experimental studies have shown that this missense change affects TP53 protein function (PMID 8080050, 10871862, 17606709,17311302, 21343334). This variant is located within a mutational hotspot that encodes the DNA-binding domain of the p53 protein. Arg213 is a highly conserved residue and multiple lines of algorithms predict deleterious effect of the p.Arg213Gln change. Therefore, we classify this c.638G>A (p.Arg213Gln) variant as pathogenic. |
| Laboratory for Molecular Medicine, |
RCV000123099 | SCV000731632 | pathogenic | Li-Fraumeni syndrome | 2020-01-10 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
| Gene |
RCV000420734 | SCV000517027 | pathogenic | not provided | 2021-11-16 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect: partial to non-functional transactivation activity, deficient in targeting the consensus binding sequencing of p53 in the regulatory region of the p21 gene, resulting in an inability to up-regulate cell cycle arrest and apoptosis (Pan 2000, Kato 2003, Monti 2011, Zhang 2014, Kotler 2018); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25268584, 16494995, 29979965, 28472496, 30224644, 28643165, 29058986, 25925845, 10871862, 14583457, 23259501, 16736287, 19468865, 8080050, 24728327, 1915267, 8492087, 21343334, 17606709, 24384472, 26270727, 26829319, 20522432, 28369373, 29076966, 18208484, 28861920, 29489754, 28724667, 30455982, 30675318, 30299350, 30720243, 30840781, 31119730, 30577483, 31481248, 31105275, 31447099, 33138793, 33818021, 17541742, 15510160) |
| Color Diagnostics, |
RCV000130072 | SCV000292157 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-06-18 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glutamine at codon 213 in the DNA binding domain 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 results in the loss of DNA binding and transactivation activity of TP53 protein (PMID: 7885831, 10871862, 12826609, 16736287, 24384472). This variant has been reported in an individual affected with Li-Fraumeni syndrome (Color internal data) and in individuals meeting the Chompret criteria of Li-Fraumeni syndrome (PMID: 17541742, 23259501). In a large pedigree that meets the Birch criteria of Li-Fraumeni-like syndrome, this variant has been shown to segregate with late-onset breast cancer, ovarian cancer, colorectal cancer, renal cell cancer, melanoma, mesothelioma and lung cancer in 12 family members (PMID: 16736287). This variant has been observed in individuals not meeting Li-Fraumeni syndrome diagnostic criteria but affected with breast cancer (PMID: 17541742, 20522432, 31119730, 32019277; Color internal data) and sarcoma (PMID: 19468865). An analysis of the IARC TP53 germline variant dataset has shown this variant to exhibit reduced penetrance (PMID: 29076966). This variant has been identified in 1/251462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. This variant may display reduced penetrance relative to typical pathogenic TP53 variants. Medical management should be considered based on the individual's personal and family history. |
| Ambry Genetics | RCV000130072 | SCV000184899 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-11-22 | criteria provided, single submitter | clinical testing | The p.R213Q pathogenic mutation (also known as c.638G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 638. The arginine at codon 213 is replaced by glutamine, an amino acid with similar properties. In one study, p.R213Q was detected in a 3-month-old boy with choroid plexus carcinoma whose unaffected father was also found to carry the alteration (Becherini et al. Neuropathol. Appl. Neurobiol. 2008 Oct;34(5):564-8). Other studies have reported this alteration in individuals with clinical histories suspicious for Li-Fraumeni syndrome (LFS) (Achatz MI et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102; Arcand SL et al. Breast Cancer Res Treat. 2008 Apr;108(3):399-408; Pinto C et al. Fam. Cancer. 2009 May;8(4):383-90; Ruijs MW et al. J. Med. Genet. 2010 Jun;47(6):421-8; Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). 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; Zerdoumi Y et al. Hum. Mol. Genet., 2017 07;26:2591-2602). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been detected in multiple families satisfying clinical diagnostic criteria for LFS to date (Ambry internal data). However, it has also been detected in individuals with atypical/mild LFS phenotypes, suggesting variable expressivity and penetrance (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as a pathogenic mutation. |
| Labcorp Genetics |
RCV000123099 | SCV000166400 | pathogenic | Li-Fraumeni syndrome | 2026-01-28 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 213 of the TP53 protein (p.Arg213Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Li-Fraumeni syndrome (LFS) or LFS-associated malignancies (PMID: 16494995, 16736287, 17541742, 18208484, 19468865, 20522432, 23259501). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 135359). 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, 16736287, 17606709, 21343334). For these reasons, this variant has been classified as Pathogenic. |
| Prevention |
RCV004745203 | SCV005365967 | pathogenic | TP53-related disorder | 2024-06-17 | no assertion criteria provided | clinical testing | The TP53 c.638G>A variant is predicted to result in the amino acid substitution p.Arg213Gln. This variant has been reported in individuals with Li-Fraumeni syndrome or related cancers (Ruijs et al. 2006. PubMed ID: 16736287; Table S1A, Monti et al. 2007. PubMed ID: 17606709; Arcand et al. 2008. PubMed ID: 17541742; Ruijs et al. 2010. PubMed ID: 20522432; Table S3, Sun et al. 2017. PubMed ID: 28724667; Table S3, Rana et al. 2019. PubMed ID: 31105275). Functional studies showed that this variant altered DNA-binding and transactivation activities (Table S1 and Table S3, Monti et al. 2011. PubMed ID: 21343334; Zhang et al. 2014. PubMed ID: 24384472; Zerdoumi et al. 2017. PubMed ID: 28369373). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and interpreted as pathogenic by most of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135359/). This variant is interpreted as pathogenic. |
| BRCAlab, |
RCV000130072 | SCV002589031 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-08-26 | no assertion criteria provided | clinical testing | |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000420734 | SCV001953963 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Clinical Genetics Laboratory, |
RCV000420734 | SCV001905965 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
| Institute of Medical Sciences, |
RCV001255672 | SCV001432237 | pathogenic | Lip and oral cavity carcinoma | 2019-04-30 | no assertion criteria provided | research | |
| Oxford Haemato- |
RCV000626448 | SCV000734838 | drug response | Poly (ADP-Ribose) polymerase inhibitor response | 2017-11-27 | no assertion criteria provided | clinical testing | |
| Pathway Genomics | RCV000144664 | SCV000189995 | pathogenic | Li-Fraumeni syndrome 1 | 2014-07-24 | no assertion criteria provided | clinical testing | |
| ITMI | RCV000122176 | SCV000086391 | not provided | not specified | 2013-09-19 | no classification provided | reference population |