ClinVar Miner

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

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Total submissions: 8
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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 colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564062 SCV000662362 likely benign Hereditary cancer-predisposing syndrome 2020-03-27 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
Color Health, Inc RCV000564062 SCV000685190 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588584 SCV000695782 likely benign not specified 2021-05-24 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. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1403G>A has been reported in the literature in individuals affected with colorectal cancer (example, Hampel_2008, Houlleberghs_2017). At-least one of these reported a microsatellite stable (MSS) and MLH1+/MSH2+MSH6+ IHC profile (Barneston_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on MMR (mismatch repair) protein function (Houlleberghs_2017). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=2; benign, n=1; VUS, n=1). At-least one submitter report a likely benign outcome reports a non-specified co-occurrence with mutation in same gene (phase unknown) supporting their classification and cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000986714 SCV001135804 benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
GeneDx RCV001582559 SCV001819075 uncertain significance not provided 2020-10-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate MMR proficiency in site-directed mutagenesis assay (Houlleberghs 2017); This variant is associated with the following publications: (PMID: 32926152, 30798936, 28922847, 28531214, 21153778, 23621914, 18809606, 19389263, 17854147, 18033691, 25637381)
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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