Submissions for variant NM_000179.3(MSH6):c.3686A>G (p.Asn1229Ser)

gnomAD frequency: 0.00001  dbSNP: rs730881807

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160697	SCV000211325	uncertain significance	not provided	2019-11-11	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30798936)
Invitae	RCV000226708	SCV000283813	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564770	SCV000669907	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-27	criteria provided, single submitter	clinical testing	The p.N1229S variant (also known as c.3686A>G), located in coding exon 8 of the MSH6 gene, results from an A to G substitution at nucleotide position 3686. The asparagine at codon 1229 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other 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.
Counsyl	RCV000663071	SCV000786143	uncertain significance	Lynch syndrome 5	2018-03-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175454	SCV001339020	uncertain significance	not specified	2022-03-20	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3686A>G (p.Asn1229Ser) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251240 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.3686A>G in individuals affected with Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have 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 classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000663071	SCV004019040	uncertain significance	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003467253	SCV004195708	uncertain significance	Endometrial carcinoma	2023-06-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998504	SCV004829215	uncertain significance	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 1229 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 been identified in 6/251240 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.