ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3217C>T (p.Pro1073Ser) (rs142254875)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115406 SCV000187203 likely benign Hereditary cancer-predisposing syndrome 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification,No disease association in small case-control study
Biesecker Lab/Human Development Section,National Institutes of Health RCV000034498 SCV000043361 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034498 SCV000493608 uncertain significance not provided 2016-07-31 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000659894 SCV000781791 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000115406 SCV000910560 benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764428 SCV000895485 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000202106 SCV000149315 likely benign not specified 2017-11-01 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.
Genetic Services Laboratory, University of Chicago RCV000202106 SCV000595855 uncertain significance not specified 2017-06-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000202106 SCV000919760 likely benign not specified 2018-09-24 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3217C>T (p.Pro1073Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 277092 control chromosomes, predominantly at a frequency of 0.0077 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 54.2 fold of 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 Ashkenazi Jewish origin. c.3217C>T has been reported in the literature in individuals affected with Lynch Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Seven 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. Based on the evidence outlined above, the variant was classified as likely benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074820 SCV000108031 likely benign Lynch syndrome 2018-10-18 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.001-0.049 (0.02)
Invitae RCV000524158 SCV000166227 benign Hereditary nonpolyposis colon cancer 2017-12-29 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202106 SCV000257242 uncertain significance not specified no assertion criteria provided research
Mendelics RCV000074820 SCV000837910 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000034498 SCV000805883 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000074820 SCV000887451 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.3217C>T has a 74.5% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.

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