ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586502 SCV000149322 uncertain significance not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3283C>T at the cDNA level, p.Arg1095Cys (R1095C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant was observed in at least one individual with early-onset endometrial cancer showing loss of MLH1 and PMS2 protein expression by immunohistochemistry (Shirts 2016). However, this variant was also observed in at least one healthy European individual undergoing whole genome sequencing (Bodian 2014); of note, the participants in the study by Bodian et al. were younger than 50 years old, thus the unaffected status of this individual may not be significant. MSH6 Arg1095Cys was observed at an allele frequency of 0.014% (18/126712) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg1095Cys is located in the ATPase domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg1095Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115413 SCV000172721 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence,Insufficient evidence
Invitae RCV000524167 SCV000260901 likely benign Hereditary nonpolyposis colon cancer 2017-12-27 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 RCV000115413 SCV000685382 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586502 SCV000695855 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3283C>T (p.Arg1095Cys) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 9/121374 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000105 (7/66732). This frequency is close the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is possibly a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until more evidence becomes available.
Center for Human Genetics, Inc RCV000412360 SCV000781792 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
ITMI RCV000121585 SCV000085781 not provided not specified 2013-09-19 no assertion provided reference population

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