ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3246G>A (p.Pro1082=) (rs3136351)

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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 RCV000163801 SCV000214384 likely benign Hereditary cancer-predisposing syndrome 2014-12-28 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724321 SCV000230868 uncertain significance not provided 2014-10-30 criteria provided, single submitter clinical testing
Invitae RCV001085889 SCV000260070 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Counsyl RCV000410558 SCV000489464 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-10-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163801 SCV000685371 likely benign Hereditary cancer-predisposing syndrome 2015-04-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000202109 SCV000917772 benign not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3246G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 8-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. To our knowledge, no occurrence of c.3246G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (CHEK2 c.1263delT , p.Ser422fsX15), providing supporting evidence for a benign role. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx RCV000724321 SCV001757089 benign not provided 2015-03-03 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000202109 SCV000257245 uncertain significance not specified no assertion criteria provided research
True Health Diagnostics RCV000163801 SCV000886689 likely benign Hereditary cancer-predisposing syndrome 2018-07-13 no assertion criteria provided clinical testing

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