Submissions for variant NM_000546.6(TP53):c.377A>G (p.Tyr126Cys)

dbSNP: rs1555526335

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547041	SCV000629816	uncertain significance	Li-Fraumeni syndrome	2024-07-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 126 of the TP53 protein (p.Tyr126Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 14965603). ClinVar contains an entry for this variant (Variation ID: 458541). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TP53 function (PMID: 11920959, 12826609, 17724467, 21343334, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001021115	SCV001182691	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-28	criteria provided, single submitter	clinical testing	The p.Y126C pathogenic mutation (also known as c.377A>G), located in coding exon 4 of the TP53 gene, results from an A to G substitution at nucleotide position 377. The tyrosine at codon 126 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TP53-related disease (personal communication). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). Multiple functional studies have shown that this alteration results in loss-of-function (Kato S et al. Proc. Natl. Acad. Sci. U.S.A. 2003 Jul;100(14):8424-9; Kotler E et al. Mol. Cell 2018 Jul;71(1):178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50(10):1381-1387). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV001021115	SCV002582098	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289730	SCV002582661	uncertain significance	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002289730	SCV003842993	uncertain significance	Li-Fraumeni syndrome 1	2023-01-10	criteria provided, single submitter	clinical testing	The TP53 c.377A>G (p.Tyr126Cys) missense change is absent in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in individuals with LFS-associated cancers (PMID: 14965603, internal data). Computational evidence supports a deleterious effect of this variant on protein function (Align GVGD = C65, BayesDel = 0.5956). 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 likely pathogenic.
Myriad Genetics, Inc.	RCV002289730	SCV004931915	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-13	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 20505364]. This variant is expected to disrupt protein structure [Myriad internal data].
GeneDx	RCV005051792	SCV005685660	pathogenic	not provided	2024-07-24	criteria provided, single submitter	clinical testing	Reported in an individual with pediatric-onset leukemia and glioma (PMID: 34479910); Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (PMID: 21343334, 12826609, 29979965, 30224644, 20505364); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30720243, 30840781, 34273903, 38862470, 21343334, 12826609, 29979965, 30224644, 20505364, 14965603, 11920959, 17724467, 12792784, 15510160, 34479910)
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785493	SCV000924065	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research