Submissions for variant NM_000179.3(MSH6):c.33C>G (p.Phe11Leu)

gnomAD frequency: 0.00001  dbSNP: rs747802641

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166008	SCV000216767	likely benign	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000679237	SCV000279089	uncertain significance	not provided	2023-10-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as a germline variant in an individual with metastatic castration-resistant prostate cancer (Carlson et al., 2020); This variant is associated with the following publications: (PMID: 22949387, 12019211, 21120944, 32997692)
Invitae	RCV001085290	SCV000624857	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166008	SCV000690350	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 11 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 been reported in an individual affected with prostate cancer (PMID: 32997692). This variant has been identified in 35/245118 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.
PreventionGenetics, part of Exact Sciences	RCV000679237	SCV000805888	uncertain significance	not provided	2017-11-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264551	SCV001442759	likely benign	not specified	2023-04-07	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.33C>G (p.Phe11Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 245118 control chromosomes, predominantly at a frequency of 0.001 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.33C>G has been reported in the literature in at least one individual affected with prostate cancer, however without strong evidence for causality (e.g., Carlson_2020). This report therefore does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and reported the variant with conflicting assessments (VUS, n = 4; likely benign, n = 2). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679237	SCV002046543	likely benign	not provided	2022-08-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995471	SCV004832231	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 11 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 35/245118 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.