Submissions for variant NM_000179.3(MSH6):c.2320C>G (p.Leu774Val)

gnomAD frequency: 0.00001  dbSNP: rs864622324

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204030	SCV000260151	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 774 of the MSH6 protein (p.Leu774Val). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 219956). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV000570810	SCV000662375	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-07	criteria provided, single submitter	clinical testing	The p.L774V variant (also known as c.2320C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2320. The leucine at codon 774 is replaced by valine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000662629	SCV000785301	uncertain significance	Lynch syndrome 5	2017-07-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000570810	SCV000904018	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 774 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 been identified in 2/251146 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553643	SCV001774578	uncertain significance	not specified	2021-07-13	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2320C>G (p.Leu774Val) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251146 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2320C>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001589090	SCV001825717	uncertain significance	not provided	2020-08-25	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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
Sema4, Sema4	RCV000570810	SCV002535724	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-26	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662629	SCV004018914	uncertain significance	Lynch syndrome 5	2023-03-28	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	RCV003997597	SCV004842061	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 774 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 been identified in 2/251146 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.