ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1049C>T (p.Ala350Val)

gnomAD frequency: 0.00003  dbSNP: rs587782331
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131253 SCV000186215 benign Hereditary cancer-predisposing syndrome 2023-10-26 criteria provided, single submitter clinical testing This alteration is classified as 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 RCV000168415 SCV000211269 likely benign not provided 2020-02-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001086248 SCV000219109 benign Hereditary nonpolyposis colorectal neoplasms 2024-02-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131253 SCV000902914 benign Hereditary cancer-predisposing syndrome 2017-01-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000168415 SCV001134385 likely benign not provided 2020-11-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212642 SCV001519616 benign not specified 2021-03-13 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1049C>T (p.Ala350Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 251258 control chromosomes. The observed variant frequency is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1049C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A recent report evaluating a tumor characteristic likelihood ratio (TCLR) in combination with a multifactorial variant prediction (MVP) model predicted this variant to have a benign outcome (Li_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=2; likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000212642 SCV001977850 benign not specified no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000168415 SCV001979311 likely benign not provided no assertion criteria provided clinical testing
PreventionGenetics, part of Exact Sciences RCV004544297 SCV004774860 likely benign MSH6-related disorder 2023-05-19 no assertion criteria provided clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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