Submissions for variant NM_000546.6(TP53):c.380C>A (p.Ser127Tyr)

dbSNP: rs730881999

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV001527086	SCV001737925	pathogenic	Li-Fraumeni syndrome 1	2021-04-20	reviewed by expert panel	curation	This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 65 (PP3_Moderate). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Transactivation assays show a low functioning allele according to Kato, et al. and there is an in vitro proliferation assay demonstrating loss of function (PS3; PMID: 12826609, PMID: 25584008). This variant has been reported in 2 probands meeting Chompret criteria (PS4; internal laboratory contributors). This variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed (PP1; internal laboratory contributor). In summary, TP53 c.380C>A (p.Ser127Tyr) meets criteria to be classified as Pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3_Moderate, PM1, PS3, PS4_Supporting, PP1.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000813247	SCV000953598	pathogenic	Li-Fraumeni syndrome	2022-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 127 of the TP53 protein (p.Ser127Tyr). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser127 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29470806; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 22109999, 29979965). 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. ClinVar contains an entry for this variant (Variation ID: 656751). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV002352420	SCV002622815	uncertain significance	Hereditary cancer-predisposing syndrome	2018-03-02	criteria provided, single submitter	clinical testing	The p.S127Y variant (also known as c.380C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 380. The serine at codon 127 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration has been reported as a somatic mutation 12 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum. Mutat. 2007 Jun;28:622-9). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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.
Myriad Genetics, Inc.	RCV001527086	SCV004933967	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].