Submissions for variant NM_000179.3(MSH6):c.3465G>T (p.Gln1155His)

gnomAD frequency: 0.00001  dbSNP: rs766817979

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465952	SCV000551183	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1155 of the MSH6 protein (p.Gln1155His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 410474). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000564013	SCV000669984	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-11	criteria provided, single submitter	clinical testing	The p.Q1155H variant (also known as c.3465G>T), located in coding exon 6 of the MSH6 gene, results from a G to T substitution at nucleotide position 3465. The glutamine at codon 1155 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000564013	SCV000910171	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 1155 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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). A different missense variant occurring at the same codon, p.Gln1155Arg is known to be disease-causing (ClinVar variation ID: 1318850). 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	RCV000985845	SCV001134432	uncertain significance	not provided	2020-08-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000564013	SCV002528030	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	curation
GeneDx	RCV000985845	SCV004022587	uncertain significance	not provided	2023-07-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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, 31925297)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003401482	SCV004121982	uncertain significance	not specified	2023-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463936	SCV004197682	uncertain significance	Endometrial carcinoma	2024-03-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001838	SCV004835074	uncertain significance	Lynch syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 1155 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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). A different missense variant occurring at the same codon, p.Gln1155Arg is known to be disease-causing (ClinVar variation ID: 1318850). 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.
PreventionGenetics, part of Exact Sciences	RCV004740240	SCV005360206	uncertain significance	MSH6-related disorder	2024-03-28	no assertion criteria provided	clinical testing	The MSH6 c.3465G>T variant is predicted to result in the amino acid substitution p.Gln1155His. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has interpretations of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/410474/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.