ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3283C>T (p.Arg1095Cys) (rs376243329)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586502 SCV000149322 uncertain significance not provided 2021-09-01 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 no damaging effect: proficient mismatch repair activity (Houlleberghs 2017); This variant is associated with the following publications: (PMID: 21120944, 17531815, 29044863, 31391288, 24448499, 31386297, 30093976, 30159786, 12522549, 28531214, 24728327, 26845104, 23621914, 31013963)
Ambry Genetics RCV000115413 SCV000172721 likely benign Hereditary cancer-predisposing syndrome 2020-02-18 criteria provided, single submitter clinical testing No disease association in small case-control study;Other data supporting benign classification
Invitae RCV001080360 SCV000260901 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-03 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000204658 SCV000266209 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Counsyl RCV000412360 SCV000488103 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115413 SCV000685382 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-12 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 1095 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with Lynch syndrome-associated cancers (PMID: 12522549, 26845104, 30093976, 31391288), breast cancer (PMID: 30159786) and an unspecified cancer (PMID: 31391288). This variant also has been observed in a pancreatic cancer case-control study in multiple unaffected individuals and absent in affected individuals (PMID: 32980694). This variant has been identified in 23/282860 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121585 SCV000695855 likely benign not specified 2021-06-21 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3283C>T (p.Arg1095Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core 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 8.4e-05 in 251452 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is approximately the same as expected for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (0.00014 vs 0.00014), supporting a benign outcome. c.3283C>T has been reported in the literature in settings of multigene cancer panel testing among individuals affected with Lynch Syndrome (example Shirts_2015, Kanchi_2014, Li_2020). One of these reports estimated the tumor characteristic likelihood ratio (TCLR) for this variant as likely benign (Li_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in an MMR (mismatch repair) assay (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 (likely benign, n=2; VUS, n=6). Some submitters cite overlapping evidence utilized in the context of this evaluation and at-least one submitter has re-classified this variant as likely benign since its previous evaluation. Based on the evidence outlined above, the variant was re-classified as likely benign.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000412360 SCV000781792 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586502 SCV001152302 uncertain significance not provided 2017-02-01 criteria provided, single submitter clinical testing
ITMI RCV000121585 SCV000085781 not provided not specified 2013-09-19 no assertion provided reference population
Clinical Genetics,Academic Medical Center RCV000586502 SCV001926147 uncertain significance not provided no assertion criteria provided clinical testing

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