Submissions for variant NM_000179.3(MSH6):c.2875C>T (p.Arg959Cys)

gnomAD frequency: 0.00001  dbSNP: rs751973865

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165958	SCV000216715	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-13	criteria provided, single submitter	clinical testing	The p.R959C variant (also known as c.2875C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2875. The arginine at codon 959 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was observed in 2/287 patients with hereditary breast and/or ovarian cancer (Caminsky NG et al. Hum Mutat, 2016 07;37:640-52). This amino acid position is well 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.
GeneDx	RCV000214010	SCV000279105	uncertain significance	not provided	2020-08-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and family history of breast and/or ovarian cancer (Caminsky 2016); This variant is associated with the following publications: (PMID: 26898890, 27067391)
Invitae	RCV000473325	SCV000551190	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165958	SCV000685327	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 959 of the MSH6 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 26898890). This variant has been identified in 5/281492 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	RCV001526922	SCV001737681	uncertain significance	not specified	2021-06-14	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2875C>T (p.Arg959Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250096 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2875C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for causality (e.g. Caminsky_2016, Schubert_2019). In addition, a somatic occurrence of c.2875C>T has been reported in at least one tumor from a patient with Lynch-Like colorectal cancer (e.g. Golubicki_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003468765	SCV004195559	uncertain significance	Endometrial carcinoma	2023-08-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995466	SCV004838900	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 959 of the MSH6 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 26898890). This variant has been identified in 5/281492 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.