Submissions for variant NM_000251.3(MSH2):c.286C>T (p.Arg96Cys)

gnomAD frequency: 0.00001  dbSNP: rs1443234544

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000580951	SCV000685075	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 96 of the MSH2 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with Extramammary Paget disease (PMID: 27487738) and breast/ovarian cancer (PMID: 32068069). This variant has been identified in 3/282534 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.
Invitae	RCV000629862	SCV000750818	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580951	SCV001177725	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	clinical testing	The p.R96C variant (also known as c.286C>T), located in coding exon 2 of the MSH2 gene, results from a C to T substitution at nucleotide position 286. The arginine at codon 96 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified as a germline alteration in 1/172 individuals with extramammary Paget disease (EMPD) (Kang Z et al. Am. J. Surg. Pathol. 2016 Nov;40:1517-1525). This alteration has also been reported in an individual affected with pancreatic ductal adenocarcinoma (Cremin C et al. Cancer Med, 2020 06;9:4004-4013). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). 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.
Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research	RCV001090210	SCV001245508	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193290	SCV001362025	uncertain significance	not specified	2019-07-26	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.286C>T (p.Arg96Cys) results in a non-conservative amino acid change located in the N-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251282 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.286C>T has been reported in the literature in one individual affected with Extramammary Paget Disease (EMPD; Kang_2016). This report does not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014) and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000580951	SCV002534510	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-26	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004001260	SCV004824307	uncertain significance	Lynch syndrome	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 96 of the MSH2 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). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in individuals affected with Extramammary Paget disease (PMID: 27487738) and breast/ovarian cancer (PMID: 32068069). This variant has been identified in 3/282534 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.