Submissions for variant NM_000179.3(MSH6):c.910G>A (p.Val304Met)

gnomAD frequency: 0.00001  dbSNP: rs876661207

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000220303	SCV000279791	uncertain significance	not provided	2024-03-19	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: 21437237)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540281	SCV000625020	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 304 of the MSH6 protein (p.Val304Met). 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: 234768). 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 with a negative predictive value of 95%. 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.
Counsyl	RCV000663285	SCV000786527	uncertain significance	Lynch syndrome 5	2018-05-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771395	SCV000903734	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-03	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 304 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 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	RCV000220303	SCV001134462	uncertain significance	not provided	2018-09-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000771395	SCV001180165	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	The p.V304M variant (also known as c.910G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 910. The valine at codon 304 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well 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.
Myriad Genetics, Inc.	RCV000663285	SCV004018859	uncertain significance	Lynch syndrome 5	2023-03-27	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV004806249	SCV005429237	uncertain significance	Lynch syndrome	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 304 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 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.