ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.73G>T (p.Ala25Ser) (rs267608026)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115442 SCV000186605 likely benign Hereditary cancer-predisposing syndrome 2017-11-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign),Other data supporting benign classification
Color RCV000115442 SCV000690476 likely benign Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000602117 SCV000744283 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-05-31 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000602117 SCV000734205 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765674 SCV000897016 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000417385 SCV000149351 likely benign not specified 2017-09-14 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago RCV000417385 SCV000595848 uncertain significance not specified 2016-01-06 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000602117 SCV000743209 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2014-10-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000417385 SCV000919764 likely benign not specified 2018-05-11 criteria provided, single submitter clinical testing Variant summary: MSH6 c.73G>T (p.Ala25Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within Non-Finnish European control individuals (37/269072) in the gnomAD database is approximately 2 fold above the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.73G>T has been reported in the literature in individuals affected with Lynch Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other potentially pathogenic variant(s) have been reported (MSH6 c.2926_2929dupCGTT; Jori_2015), providing supporting evidence for a benign role. Two independent publications report functional evidence that the variant is MMR proficient (Drost_2011, Houlleberghs_2017). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, including VUS and likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000524214 SCV000219021 likely benign Hereditary nonpolyposis colon cancer 2017-12-18 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000417385 SCV000539705 uncertain significance not specified 2017-01-25 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in HGMD, classified as DM?. It has been seen in 2 breast cancer families. In one in vitro study the variant was shown to be mismatch repair proficient. In another paper it is predicted to be neutral. The variant has a Max MAF of 0.03% in ExAC (16 alleles) and 0.03% in gnomAD (35 alleles). It is classified with 3 stars in ClinVar as VUS by an expert panel (InSiGHT) and U Wash, and as Likely benign by GeneDx, Invitae, and Ambry. This region is not conserved and 2 mammals have a Ser at this position.
University of Washington Department of Laboratory Medicine,University of Washington RCV000075031 SCV000266212 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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