ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.115G>C (p.Gly39Arg) (rs751838296)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000459919 SCV000551191 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-03 criteria provided, single submitter clinical testing
GeneDx RCV001721501 SCV000565207 likely benign not provided 2018-03-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567789 SCV000662380 likely benign Hereditary cancer-predisposing syndrome 2019-02-25 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Counsyl RCV000663030 SCV000786063 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-02-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000567789 SCV000904011 likely benign Hereditary cancer-predisposing syndrome 2017-06-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000481267 SCV001572451 likely benign not specified 2021-04-04 criteria provided, single submitter clinical testing Variant summary: MSH6 c.115G>C (p.Gly39Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 232766 control chromosomes, predominantly at a frequency of 0.00087 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6 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 South Asian origin. To our knowledge, no occurrence of c.115G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five 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 (likely benign, n=3; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.

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