Submissions for variant NM_000179.3(MSH6):c.2830A>G (p.Ile944Val)

gnomAD frequency: 0.00001  dbSNP: rs878853723

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231932	SCV000283769	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571874	SCV000669908	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-24	criteria provided, single submitter	clinical testing	The p.I944V variant (also known as c.2830A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2830. The isoleucine at codon 944 is replaced by valine, an amino acid with highly similar properties. 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	RCV000571874	SCV000905510	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 944 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 been identified in 3/250456 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.
GeneDx	RCV001589169	SCV001814181	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	Not observed at a 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: 17531815, 21120944, 28944238)
PreventionGenetics, part of Exact Sciences	RCV004529388	SCV004108516	uncertain significance	MSH6-related disorder	2023-05-03	criteria provided, single submitter	clinical testing	The MSH6 c.2830A>G variant is predicted to result in the amino acid substitution p.Ile944Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48027952-A-G). In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/237168/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003463639	SCV004195651	uncertain significance	Endometrial carcinoma	2023-07-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998722	SCV004836354	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 944 of the MSH6 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Splice site prediction tools suggest that this variant may impact RNA splicing. However, this prediction has not been confirmed in published RNA studies. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250456 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000581651	SCV000691932	uncertain significance	not specified		no assertion criteria provided	clinical testing