ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1932G>C (p.Arg644Ser) (rs34938432)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166227 SCV000217006 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000524127 SCV000254286 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000219792 SCV000279099 likely benign not specified 2017-10-16 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.
Counsyl RCV000409155 SCV000488252 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-02-04 criteria provided, single submitter clinical testing
Mendelics RCV000074697 SCV000837891 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000166227 SCV000910867 likely benign Hereditary cancer-predisposing syndrome 2015-11-10 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000074697 SCV000914309 uncertain significance Lynch syndrome 2019-01-30 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000219792 SCV000917765 likely benign not specified 2018-06-04 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1932G>C (p.Arg644Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within African control individuals in the gnomAD database is approximately 7 fold above 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 origin. c.1932G>C has been reported in the literature in individuals affected with Lynch Syndrome and pancreatic cancer. 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 with conflicting assessments, including likely benign (2x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000409155 SCV001135813 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing

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