Submissions for variant NM_000546.6(TP53):c.784G>A (p.Gly262Ser)

gnomAD frequency: 0.00002  dbSNP: rs200579969

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000463102	SCV001432164	uncertain significance	Li-Fraumeni syndrome	2020-09-04	reviewed by expert panel	curation	This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 25 or higher (PP3). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor (SCV000686773.2). In summary, the clinical significance of TP53 c.784G>A (p.Gly262Ser) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PP3, BS2_Supporting.
Ambry Genetics	RCV000129643	SCV000184438	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	The p.G262S variant (also known as c.784G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 784. The glycine at codon 262 is replaced by serine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression and has no dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387).This alteration has been reported in a BRCA1/2-negative woman diagnosed with breast cancer at age 42 and in her unaffected sister (Li J et al. J Med Genet. 2016 Jan;53(1):34-42) and also in a proband with breast cancer diagnosed at age 46 and 56 who underwent multigene panel testing (Bradbury AR et al. JCO Precis Oncol 2018 Apr;2). 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	RCV000463102	SCV000545274	uncertain significance	Li-Fraumeni syndrome	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 262 of the TP53 protein (p.Gly262Ser). This variant is present in population databases (rs200579969, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 26534844, 32095738). ClinVar contains an entry for this variant (Variation ID: 141228). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 12826609, 29979965, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
GeneDx	RCV000590725	SCV000567260	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	Published functional studies are conflicting: non-functional transactivation, no effect on growth suppression (PMID: 29979965, 12826609, 30224644); Observed in an individual with breast cancer and her unaffected sister (PMID: 26534844); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8023157, 12826609, 7955036, 16907706, 10719737, 11161397, 14670539, 14559903, 9719952, 22768918, 22678923, 27564104, 20025891, 16818665, 31016814, 30840781, 30352134, 29979965, 30224644, 35328131, 30661751, 34273903, 32014905, 15510160, 26534844)
Color Diagnostics, LLC DBA Color Health	RCV000129643	SCV000686773	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 262 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies are conflicting for this variant with the variant shown to be defective for transcriptional transactivation in yeast (PMID: 12826609) but functional in human cell growth suppression and proliferation assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 26534844, 32095738). This variant has been identified in 3/276106 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590725	SCV000697449	uncertain significance	not provided	2016-06-20	criteria provided, single submitter	clinical testing	Variant summary: The TP53 c.784G>A (p.Gly262Ser) variant involves the alteration of a conserved nucleotide located in the DNA binding domain, which is the target of 90% of p53 mutations found in human cancers (UMD database). 5/5 in silico tools predict a damaging outcome for this variant. This variant has been reported one family with multiple breast cancer patients, however, no detailed co-segregation analysis was performed. This variant has also been reported in numerous types of tumor samples with or without confirmed somatic status. This variant is absent in 89212 control chromosomes from ExAC. A reputable database (IARC) has reported this variant to have median transcription activity <=20% and classified it as non-functional. Other nearby missense variants have also been reported, namely p.Asn263Asp, p.Gly266Val and p.Arg267Trp; they all have been reported by a lab in ClinVar, the former two classified as uncertain significance and the last as likely pathogenic. One clinical diagnostic laboratory classified this variant as VUS. Taken together, this variant is currently classified as VUS-possibly pathogenic.
Sema4, Sema4	RCV000129643	SCV002532710	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-30	criteria provided, single submitter	curation
Baylor Genetics	RCV004567090	SCV005054333	uncertain significance	Adrenocortical carcinoma, hereditary	2024-02-26	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535496	SCV001749445	not provided	Li-Fraumeni syndrome 1		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-07-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV003415944	SCV004115102	uncertain significance	TP53-related disorder	2024-04-20	no assertion criteria provided	clinical testing	The TP53 c.784G>A variant is predicted to result in the amino acid substitution p.Gly262Ser. This variant has been reported in an individual with breast cancer as well as in an unaffected sibling (Figure 1, Li et al. 2016. PubMed ID: 26534844). An in silico quantitative model predicts this variant to be pathogenic (Table S1, Fortuno et al. 2019. PubMed ID: 30840781), but has also been predicted to be a variant of uncertain significance by another group (Evans et al. 2019. PubMed ID: 31016814). This variant is reported in 0.0024% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and has been reported in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/141228/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.