Total submissions: 11
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000167874 | SCV007113941 | likely pathogenic | Li-Fraumeni syndrome | 2025-12-05 | reviewed by expert panel | curation | The NM_000546.6:c.589G>A variant in TP53 is a missense variant predicted to cause substitution of valine by methionine at amino acid 197 (p.Val197Met). This variant has been reported in 1 family meeting Revised Chompret criteria and reported in 1 additional individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal contributors). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, ClinVar SCV001186711.5, Internal lab contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation and loss of growth suppression activity, indicating that this variant impacts protein function (PS3_Moderate; PMIDs: 12826609, 30224644, 29979965). This variant has three 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 (2–9 somatic occurrences; PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li-Fraumeni syndrome, based on the ACMG/AMP criteria applied as specified by the ClinGen TP53 VCEP: PS4_Supporting, PP4, PM2_Supporting, PS3_Moderate, PM1_Supporting (Bayesian Points: 6; VCEP specifications version 2.3). |
| Institute for Genomic Medicine |
RCV000167874 | SCV007449408 | uncertain significance | Li-Fraumeni syndrome | 2022-10-25 | 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_Moderate; PMIDs:12826609, 30224644, 29979965, 21343334). This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4_Supporting; PMIDs:16494995, 23259501, 31321604, 25945745). This variant is absent from or present at an exceedingly low frequency in gnomAD, a large-scale control population database (ACMG/AMP: PM2_Supporting). |
| Gene |
RCV006263709 | SCV007121347 | likely pathogenic | not provided | 2025-05-29 | criteria provided, single submitter | clinical testing | This variant has been identified in individuals with a personal and family history of Li-Fraumeni-related cancers (PMID: 16494995, 25945745); Published functional studies demonstrate a damaging effect: partially functional or loss of transactivation for critical p53 reporters and impaired growth suppression activity (PMID: 12826609, 30224644, 29979965, 39060302, 21343334); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29979965, 30720243, 30840781, 34273903, 15510160, 14559903, 12826609, 38295319, 23259501, 21343334, 24038938, 39060302, 36551569, 30224644, 16494995, 25945745, 31321604) |
| Molecular Pathology, |
RCV000167874 | SCV006277636 | likely pathogenic | Li-Fraumeni syndrome | 2025-05-01 | criteria provided, single submitter | clinical testing | |
| Center for Genomic Medicine, |
RCV005230025 | SCV005871949 | likely oncogenic | Neoplasm | 2025-03-04 | criteria provided, single submitter | clinical testing | |
| Myriad Genetics, |
RCV002288770 | SCV004932550 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-15 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16494995, 23259501, 31321604; Myriad internal data]. |
| All of Us Research Program, |
RCV000167874 | SCV004825089 | uncertain significance | Li-Fraumeni syndrome | 2023-08-15 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV002288770 | SCV002582358 | uncertain significance | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV001024656 | SCV002582050 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV001024656 | SCV001186711 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2025-07-28 | criteria provided, single submitter | clinical testing | The p.V197M variant (also known as c.589G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 589. The valine at codon 197 is replaced by methionine, an amino acid with highly similar properties. This variant has been identified in individuals with features consistent with Li-Fraumeni or Li-Fraumeni-Like criteria (Achatz M et al., Cancer Lett. 2007 Jan; 245(1-2):96-102; Fortes F et al. Braz. J. Med. Biol. Res. 2015 Jul;48(7):610-5; external communication). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation capacity in yeast based assays (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):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). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000167874 | SCV000218520 | pathogenic | Li-Fraumeni syndrome | 2025-01-27 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 197 of the TP53 protein (p.Val197Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni (PMID: 16494995, 31321604; internal data). ClinVar contains an entry for this variant (Variation ID: 188060). 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: 21343334). This variant disrupts the p.Val197 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 33818021), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |