ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.491A>C (p.His164Pro) (rs146469162)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131540 SCV000186538 likely benign Hereditary cancer-predisposing syndrome 2020-09-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);No disease association in small case-control study
GeneDx RCV000656888 SCV000211257 likely benign not provided 2021-01-14 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23621914, 25186627)
Invitae RCV001085010 SCV000283845 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-24 criteria provided, single submitter clinical testing
Counsyl RCV000662620 SCV000785283 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-06-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656888 SCV000888291 likely benign not provided 2019-07-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131540 SCV000903020 likely benign Hereditary cancer-predisposing syndrome 2016-02-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212631 SCV000917751 likely benign not specified 2021-04-16 criteria provided, single submitter clinical testing Variant summary: MSH6 c.491A>C (p.His164Pro) results in a non-conservative amino acid change located in the PWWP domain (IPR000313) of 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 282812 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 8.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.491A>C has been reported in the literature in an individual affected with breast cancer (Tung_2015). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=4) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

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