ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1403G>A (p.Arg468His) (rs41295268)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074654 SCV000107856 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Invitae RCV000524110 SCV000551260 likely benign Hereditary nonpolyposis colon cancer 2019-08-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564062 SCV000662362 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-20 criteria provided, single submitter clinical testing Conflicting evidence
Color RCV000564062 SCV000685190 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588584 SCV000695782 uncertain significance not specified 2019-05-01 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1403G>A (p.Arg468His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of 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 3.2e-05 in 253156 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1403G>A, has been reported in the literature in individuals affected with colorectal cancer (Hampel_2008, Houlleberghs_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. In addition, at least one study reporting the result of genetic screen indicated this variant does not impact on MMR (mismatch repair) protein function (Houlleberghs_2017). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. An expert panel (InSIGHT) submitter classified this variant as likely benign in 2013 citing Multifactorial likelihood analysis posterior probability between 0.001-0.049. Based on the evidence outlined above, the variant was classified as as VUS-possibly benign until additional information becomes available.
Mendelics RCV000986714 SCV001135804 benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148649 SCV000190364 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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