Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000991141 | SCV001142539 | likely pathogenic | Li-Fraumeni syndrome | 2024-08-05 | reviewed by expert panel | curation | The NM_000546.6:c.1031T>C variant in TP53 is a missense variant predicted to cause substitution of leucine by proline at amino acid 344 (p.Leu344Pro). This variant has been reported in 1 proband meeting Classic criteria, and 1 proband 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: 8649785, 20522432). This variant has an allele frequency of 6.195e-7 (1/1614076 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (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 (PMIDs: 12826609, 30224644, 29979965) (PS3). Computational predictor scores (BayesDel = 0.4856; Align GVGD = Class 65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PS3, PS4_Supporting (Bayesian Points: 8; VCEP specifications version 2.0; 7/24/2024). |
| Labcorp Genetics |
RCV000991141 | SCV005837611 | pathogenic | Li-Fraumeni syndrome | 2025-01-23 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 344 of the TP53 protein (p.Leu344Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 8649785, 17606709, 20522432). ClinVar contains an entry for this variant (Variation ID: 12375). 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: 10064694, 17606709, 20128691). For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV000013174 | SCV004932457 | pathogenic | Li-Fraumeni syndrome 1 | 2024-02-21 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9704930, 9704931, 27754743]. 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: 8649785]. |
| Baylor Genetics | RCV003473083 | SCV004204291 | likely pathogenic | Adrenocortical carcinoma, hereditary | 2021-06-13 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002390102 | SCV002699871 | pathogenic | Hereditary cancer-predisposing syndrome | 2015-11-10 | criteria provided, single submitter | clinical testing | The p.L344P pathogenic mutation (also known as c.1031T>C), located in coding exon 9 of the TP53 gene, results from a T to C substitution at nucleotide position 1031. The leucine at codon 344 is replaced by proline, an amino acid with some similar properties. This alteration occurs at a well-characterized residue involved in the tetramerization of the p53 protein (Mateu and Fersht, EMBO J. 1998 May; 17(10):2748-58). This alteration has been identified in families meeting clinical criteria for Li-Fraumeni syndrome with a tumor spectrum including osteosarcomas, leiomyosarcomas, and early onset breast cancer (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9;Varley J et al., Oncogene 1996 Jun; 12(11):2437-42 ). Evidence from both functional and structural analyses indicate that this alteration is structurally unstable and unable to form tetramers (Ishioka C et al., Oncogene 1995 Apr; 10(8):1485-92; Davison T et al., Oncogene 1998 Aug; 17(5):651-6). Additional functional studies conducted in both yeast and mammalian cells have demonstrated that this alteration produces a protein that cannot activate transcription, is defective in DNA binding, suppression of cell growth, and induction of apoptosis (Monti P et al., Mol. Cancer Res. 2011 Mar; 9(3):271-9. Malcikova Jet al., Biol. Chem. ; 391(2-3):197-205; Lomax M et al., Oncogene 1998 Aug; 17(5):643-9). Based on the available evidence, p.L344P is classified as a pathogenic mutation. |
| Key Laboratory of Carcinogenesis and Cancer Invasion, |
RCV003996091 | SCV004046823 | likely pathogenic | Adrenal cortex carcinoma | no assertion criteria provided | clinical testing | ||
| OMIM | RCV000013174 | SCV000033421 | pathogenic | Li-Fraumeni syndrome 1 | 1999-10-01 | no assertion criteria provided | literature only |