Submissions for variant NM_000179.3(MSH6):c.3836G>A (p.Ser1279Asn)

dbSNP: rs864622400

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000205628	SCV000260488	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000481950	SCV000565236	uncertain significance	not provided	2023-03-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense 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: 22949387, 17531815, 21120944)
Ambry Genetics	RCV000562735	SCV000662359	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	The p.S1279N variant (also known as c.3836G>A), located in coding exon 9 of the MSH6 gene, results from a G to A substitution at nucleotide position 3836. The serine at codon 1279 is replaced by asparagine, an amino acid with highly similar properties. This alteration is observed in an individual whose colon tumor demonstrated normal mismatch repair protein expression on immunohistochemistry (IHC) (Ambry internal data). This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000562735	SCV000685449	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1279 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 breast/ovarian cancer (PMID: 34359559). This variant has been identified in 1/250898 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.
Counsyl	RCV000662811	SCV000785646	uncertain significance	Lynch syndrome 5	2017-10-18	criteria provided, single submitter	clinical testing
Mendelics	RCV002247633	SCV002518282	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662811	SCV004018897	likely benign	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481950	SCV004222015	uncertain significance	not provided	2023-01-09	criteria provided, single submitter	clinical testing	This variant has not been described in online databases. The frequency of this variant in the general population, 0.000004 (1/250898 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer and breast cancer (PMID: 32658311 (2011)). In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer as well as in an unaffected control individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH6)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997619	SCV004835150	uncertain significance	Lynch syndrome	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 1279 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 breast/ovarian cancer (PMID: 34359559). This variant has been identified in 1/250898 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.