ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3217C>T (p.Pro1073Ser) (rs142254875)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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)
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.
Invitae RCV001084149 SCV000166227 benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115406 SCV000187203 benign Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study;Subpopulation frequency in support of benign classification;Other data supporting benign classification
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034498 SCV000493608 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000202106 SCV000595855 uncertain significance not specified 2017-06-09 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659894 SCV000781791 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034498 SCV000805883 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing
Mendelics RCV000074820 SCV000837910 uncertain significance Lynch syndrome 2018-07-02 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.
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
Color RCV000115406 SCV000910560 benign Hereditary cancer-predisposing syndrome 2015-11-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000202106 SCV000919760 likely benign not specified 2019-10-31 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3217C>T (p.Pro1073Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of 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 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 HNPCC or colorectal cancer (Devlin_2008, Okkels_2012, Haraldsdottir_2017). 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. Eleven ClinVar submitters (evaluation after 2014) classified the variant as benign (2x), likely benign (3x) and uncertain significance (6x). Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000659894 SCV001302732 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-01 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Biesecker Lab/Clinical Genomics 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202106 SCV000257242 uncertain significance not specified no assertion criteria provided research

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