ClinVar Miner

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

dbSNP: rs730881999
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Total submissions: 4
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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.
Invitae 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].

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