ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.926C>G (p.Ser309Cys) (rs544222338)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656891 SCV000149355 uncertain significance not provided 2018-08-16 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.926C>G at the cDNA level, p.Ser309Cys (S309C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant was observed in at least one individual with advanced cancer (Mandelker 2017). MSH6 Ser309Cys was observed at an allele frequency of 0.23% (71/30,780) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located at a phosphoserine site and in a nuclear localization signal (UniProt, Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Ser309Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115446 SCV000215268 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV001089225 SCV000283860 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212637 SCV000592578 uncertain significance not specified 2016-07-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212637 SCV000601622 uncertain significance not specified 2016-12-24 criteria provided, single submitter clinical testing
Color RCV000115446 SCV000902781 likely benign Hereditary cancer-predisposing syndrome 2016-11-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212637 SCV001360587 likely benign not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: MSH6 c.926C>G (p.Ser309Cys) 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 0.0003 in 251308 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Non-Polyposis Colon Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.926C>G has been reported in the literature in individual(s) affected with advanced cancer (Mandelker_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Non-Polyposis Colon Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as likely benign (2x) and uncertain significance (4x). Based on the evidence outlined above, the variant was classified as likely benign.

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