Submissions for variant NM_000179.3(MSH6):c.3974A>G (p.Lys1325Arg)

gnomAD frequency: 0.00003  dbSNP: rs876658189

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219276	SCV000273110	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-24	criteria provided, single submitter	clinical testing	The p.K1325R variant (also known as c.3974A>G), located in coding exon 9 of the MSH6 gene, results from an A to G substitution at nucleotide position 3974. The lysine at codon 1325 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000588179	SCV000568972	uncertain significance	not provided	2023-11-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17531815, 21120944, 12019211)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000547600	SCV000624952	benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001358663	SCV000695899	uncertain significance	not specified	2021-03-22	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3974A>G (p.Lys1325Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 247380 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3974A>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000219276	SCV000903217	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 1325 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588179	SCV001134449	uncertain significance	not provided	2019-06-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000219276	SCV002536303	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-26	criteria provided, single submitter	curation
Baylor Genetics	RCV003462409	SCV004195752	uncertain significance	Endometrial carcinoma	2023-05-31	criteria provided, single submitter	clinical testing