Submissions for variant NM_000179.3(MSH6):c.3782C>T (p.Ala1261Val)

gnomAD frequency: 0.00001  dbSNP: rs773171352

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165125	SCV000215835	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing	The p.A1261V variant (also known as c.3782C>T), located in coding exon 8 of the MSH6 gene, results from a C to T substitution at nucleotide position 3782. The alanine at codon 1261 is replaced by valine, an amino acid with similar properties. This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000459296	SCV000551068	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165125	SCV000690397	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1261 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset breast cancer (PMID: 25186627). This variant has been identified in 1/251220 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	RCV001527033	SCV001737855	uncertain significance	not specified	2021-05-26	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3782C>T (p.Ala1261Val) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251220 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3782C>T has been reported in the literature in one individual affected with breast cancer (Tung_2014). The report does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003995394	SCV004835138	uncertain significance	Lynch syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1261 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset breast cancer (PMID: 25186627). This variant has been identified in 1/251220 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.