Submissions for variant NM_000179.3(MSH6):c.2776C>T (p.Leu926Phe)

gnomAD frequency: 0.00001  dbSNP: rs587781318

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129055	SCV000183753	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-21	criteria provided, single submitter	clinical testing	The p.L926F variant (also known as c.2776C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2776. The leucine at codon 926 is replaced by phenylalanine, 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.
GeneDx	RCV000212670	SCV000211302	uncertain significance	not provided	2018-11-19	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.2776C>T at the cDNA level, p.Leu926Phe (L926F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Leu926Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Lever domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Leu926Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000205831	SCV000261599	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212670	SCV000889475	uncertain significance	not provided	2018-03-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129055	SCV001347196	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 926 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 MSH6-related disorders in the literature. This variant has been identified in 1/250966 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	RCV003398753	SCV004122913	uncertain significance	not specified	2023-10-16	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2776C>T (p.Leu926Phe) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250966 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2776C>T has been reported in the literature in individuals affected with hereditary Cancer (Bhai_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 34326862). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=1) and VUS (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997476	SCV004836265	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 926 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 MSH6-related disorders in the literature. This variant has been identified in 1/250966 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.