Submissions for variant NM_000179.3(MSH6):c.899G>A (p.Arg300Gln)

gnomAD frequency: 0.00002  dbSNP: rs55760494

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000199066	SCV000254336	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214218	SCV000274179	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-24	criteria provided, single submitter	clinical testing	The p.R300Q variant (also known as c.899G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 899. The arginine at codon 300 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is well 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.
GeneDx	RCV000586061	SCV000279809	uncertain significance	not provided	2023-09-10	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; This variant is associated with the following publications: (PMID: 35449176, 21437237, 25186627, 36243179)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586061	SCV000695932	uncertain significance	not provided	2016-02-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586061	SCV000889509	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000039 (5/129052 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a somatic variant in a colorectal adenocarcinoma tumor (PMID: 30575961 (2019)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as unaffected controls (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.
Color Diagnostics, LLC DBA Color Health	RCV000214218	SCV000911931	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 300 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 hereditary cancer in the literature. This variant has been identified in 7/282686 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267932	SCV002552287	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462324	SCV004197647	uncertain significance	Endometrial carcinoma	2023-10-10	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491942	SCV004239329	uncertain significance	Breast and/or ovarian cancer	2022-10-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997003	SCV004834879	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 300 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 as a germline variant in individuals affected with hereditary cancer in the literature. This variant has been identified in 7/282686 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.