ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.124C>T (p.Pro42Ser) (rs34014629)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131942 SCV000186998 likely benign Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000524105 SCV000253087 likely benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000410444 SCV000488256 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-02-09 criteria provided, single submitter clinical testing
GeneDx RCV000422207 SCV000513671 likely benign not specified 2017-10-12 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.
Integrated Genetics/Laboratory Corporation of America RCV000422207 SCV000695777 likely benign not specified 2019-05-09 criteria provided, single submitter clinical testing Variant summary: MSH6 c.124C>T (p.Pro42Ser) 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, and two independent tools developed and reported in the literature predict the variant to be neutral (Terui_2013, Ali_2012). The variant allele was found at a frequency of 0.00011 in 227574 control chromosomes, predominantly at a frequency of 0.0019 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 13 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 a benign polymorphism found primarily in populations of African or African-American origin. Though the variant, c.124C>T, has been reported in the literature in individuals affected with colorectal cancer or with suspected Lynch Syndrome (Hampel_2005, Yurgelun_2015, da Silva_2015, Rossi_ 2017), however 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with three laboratories classifying the variant as likely benign, while one calling it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000131942 SCV000902798 likely benign Hereditary cancer-predisposing syndrome 2015-09-30 criteria provided, single submitter clinical testing
Mendelics RCV000410444 SCV001135775 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing

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