ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3647-6T>C (rs182871847)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000408958 SCV000488879 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-07-11 criteria provided, single submitter clinical testing
Invitae RCV000471309 SCV000561537 benign Hereditary nonpolyposis colon cancer 2017-10-20 criteria provided, single submitter clinical testing
Color RCV000580466 SCV000685426 likely benign Hereditary cancer-predisposing syndrome 2015-11-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781605 SCV000919777 benign not specified 2018-12-04 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3647-6T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 245942 control chromosomes, predominantly at a frequency of 0.00091 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. 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.3647-6T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. 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.

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