Total submissions: 14
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000473145 | SCV006279847 | pathogenic | Li-Fraumeni syndrome | 2025-06-05 | reviewed by expert panel | curation | The NM_000546.6: c.329G>T variant in TP53 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 110 (p.Arg110Leu). This variant has been reported in 3 unrelated families meeting Revised Chompret criteria. Based on this evidence, this variant scores 1.5 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; PMID: 30875412; Internal lab contributors). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with a strongly LFS-associated cancer totaling 4 phenotype points (PS2; Internal lab contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; Internal contributors). This variant has an allele frequency of 0.000001240 (2/1612260 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has a subpopulation allele frequency of <0.00004 in all non-bottleneck populations with 2 or more alleles present (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has [XX] somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (≥ 10 somatic occurrences, PMID: 30311369) (PM1). Computational predictor scores (BayesDel = 0.213246; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS2, PS3, PM1, PP1, PP3, PM2_Supporting, PS4_Supporting. (Bayesian Points: 14; VCEP specifications version 2.3) |
| Institute for Genomic Medicine |
RCV006254060 | SCV007104533 | tier i - strong | Adenocarcinoma of the large intestine | 2023-10-16 | criteria provided, single submitter | clinical testing | Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in colorectal adenocarcinoma, 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: 12826609). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 22810696, 24078161, 27325016, 28197804, 33924934). |
| Center for Genomic Medicine, |
RCV005230382 | SCV005871972 | oncogenic | Neoplasm | 2025-03-04 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004999438 | SCV005625956 | pathogenic | not provided | 2024-08-29 | criteria provided, single submitter | clinical testing | The TP53 c.329G>T (p.Arg110Leu) variant has been reported in the published literature in several individuals/families affected with LFS-associated cancers (PMIDs: 18511570 (2008), 29625052 (2018), 30875412 (2019), 34709361 (2021), 34863587 (2022), 35511670 (2022), 35974385 (2022), 38933650 (2024)). It was also identified in an individual with different primary cancers who also carried a deleterious variant in the BRCA2 gene (PMID: 17624602 (2007)). This variant was described as a leukemogenic driver mutation (PMID: 33057201 (2020)) and functional studies have shown that it significantly reduced transactivation/DNA-binding activity and reduced apoptosis (PMIDs: 9290701 (1997), 9667734 (1998), 12826609 (2003) and The TP53 Database (https://tp53.cancer.gov/)), 16778209 (2006), 17724467 (2008), 20505364 (2010), 24076587 (2014)). Another study observed this variant to cause protein aggregation (PMID: 21445056 (2011)). The frequency of this variant in the general population, 0.0000066 (1/152174 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. |
| Juno Genomics, |
RCV002289602 | SCV005416886 | likely pathogenic | Li-Fraumeni syndrome 1 | criteria provided, single submitter | clinical testing | Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. | |
| Myriad Genetics, |
RCV002289602 | SCV004931431 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-12 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 20505364, 24076587, 29979965]. |
| Laboratory for Molecular Medicine, |
RCV000473145 | SCV004847790 | likely pathogenic | Li-Fraumeni syndrome | 2019-12-03 | criteria provided, single submitter | clinical testing | The p.Arg110Leu variant in TP53 has been reported in 2 individuals with features of Li-Fraumeni syndrome (Rines 1998, Bougeard 2008). This variant has also been reported in ClinVar (Variation ID 406597) and was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Another variant involving this codon (p.Arg110Pro) has been identified in individuals with Li-Fraumeni syndrome (Variation ID 233627). In vitro functional studies support an impact on protein function (Mizuarai 2006, Grochova 2008, Xu 2011). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP Criteria applied: PM2, PM5, PS3_Supporting, PS4_Supporting. |
| Genome- |
RCV002289602 | SCV002583070 | likely pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV000492590 | SCV002582408 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000492590 | SCV000691588 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-01-14 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with leucine at codon 110 in the DNA binding domain of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown the mutant protein to be defective in DNA binding and transactivation activity (PMID 9290701, 12826609, 17724467, 24076587) and non-functional in cell growth assay (PMID: 29979965). This variant has been reported in multiple individuals affected with affected with Li-Fraumeni syndrome (PMID: 9667734, 18511570; ClinVar SCV000545344.5). This variant has been observed to de de novo in an individual affected with Li-Fraumeni syndrome-associated cancers (ClinVar SCV000545344.5). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same amino acid position, p.Arg110Pro, is known to be disease-causing (ClinVar variation ID: 233627), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Ambry Genetics | RCV000492590 | SCV000581121 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2015-11-05 | criteria provided, single submitter | clinical testing | The p.R110L variant (also known as c.329G>T), located in coding exon 3 of the TP53 gene, results from a G to T substitution at nucleotide position 329. The arginine at codon 110 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in one study as a known germline mutation from a cohort of Li-Fraumeni patient samples used for analysis of technique of two-dimentional gene scanning (Rines RD et al. Carcinogenesis 1998 Jun;19(6):979-84). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity but no dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). In addition, two other alterations (p.R110H and p.R110P) have been reported at this position in patients with breast cancer and/or family history meeting classic Li-Fraumeni syndrome criteria (Alsner et al. Clin Cancer Res. 2000. 6:3923-3931; Masciari et al. Genet Med. 2011.13(7):651-7; Rath MG et al. Breast Cancer Res. Treat. 2013 May;139(1):193-8). This variant was previously reported in the SNPDatabase as rs11540654. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 200000 alleles tested) in our clinical cohort, and has been found in individuals meeting clinical diagnostic criteria for Li-Fraumeni syndrome (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000473145 | SCV000545344 | pathogenic | Li-Fraumeni syndrome | 2024-11-11 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 110 of the TP53 protein (p.Arg110Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (LFS) (PMID: 9667734, 18511570; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 406597). 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: 9290701, 16778209, 17724467, 21445056, 24076587). This variant disrupts the p.Arg110 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 21552135, 23894400, 23897043, 24076587). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Key Laboratory of Carcinogenesis and Cancer Invasion, |
RCV004000748 | SCV004046832 | likely pathogenic | Adrenal cortex carcinoma | no assertion criteria provided | clinical testing | ||
| German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785348 | SCV000923916 | likely pathogenic | Ovarian neoplasm | 2018-12-01 | no assertion criteria provided | research |