Submissions for variant NM_000546.6(TP53):c.376T>G (p.Tyr126Asp)

dbSNP: rs886039483

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255685	SCV000322113	likely pathogenic	not provided	2019-06-03	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29979965, 11896595, 20668451, 21343334, 22006311, 28234344, 27189670, 14559903, 12826609, 11429705, 11229518, 21796119, 23525077, 23297126, 23103869)
Ambry Genetics	RCV000568595	SCV000672378	uncertain significance	Hereditary cancer-predisposing syndrome	2017-02-10	criteria provided, single submitter	clinical testing	The p.Y126D variant (also known as c.376T>G) is located in coding exon 4 of the TP53 gene. The tyrosine at codon 126 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 4. This alteration has been reported in an individual with a personal history of both breast and peritoneal cancer and a family history of breast or ovarian cancer (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A., 2011 Nov;108:18032-7). This variant is located in the DNA binding domain of the TP53 protein and is reported to exhibit loss of transactivation capacity in yeast-based functional studies. (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Campomenosi P et al. Oncogene, 2001 Jun;20:3573-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705124	SCV000834106	pathogenic	Li-Fraumeni syndrome	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 126 of the TP53 protein (p.Tyr126Asp). 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 syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 265333). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TP53 function (PMID: 11229518, 11429705, 12826609, 29979965, 30224644). This variant disrupts the p.Tyr126 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 14965603), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV004021027	SCV004930463	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]. This variant is expected to disrupt protein structure [Myriad internal data].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785482	SCV000924054	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research