Submissions for variant NM_000179.3(MSH6):c.2355T>A (p.His785Gln)

dbSNP: rs1060502942

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464632	SCV000551289	benign	Hereditary nonpolyposis colorectal neoplasms	2024-10-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566667	SCV000670076	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	The p.H785Q variant (also known as c.2355T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 2355. The histidine at codon 785 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health	RCV000566667	SCV000685282	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-16	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 785 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	RCV000759132	SCV000888254	uncertain significance	not provided	2020-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000759132	SCV002526373	uncertain significance	not provided	2023-10-11	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: 17531815, 21120944)
All of Us Research Program, National Institutes of Health	RCV004001857	SCV004834254	uncertain significance	Lynch syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 785 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.
Baylor Genetics	RCV004568057	SCV005054893	uncertain significance	Endometrial carcinoma	2024-02-26	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV005055114	SCV005689154	uncertain significance	Lynch syndrome 5	2025-01-22	criteria provided, single submitter	clinical testing	The MSH6 c.2355T>A p.(His785Gln) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools predict a benign effect of this variant on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.