ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1054G>A (p.Val352Ile) (rs730881787)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656893 SCV000211271 likely benign not provided 2021-01-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25111426, 28135145)
Ambry Genetics RCV000160662 SCV000212768 likely benign Hereditary cancer-predisposing syndrome 2019-05-01 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000656893 SCV000230040 uncertain significance not provided 2014-11-20 criteria provided, single submitter clinical testing
Invitae RCV001082336 SCV000283697 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-22 criteria provided, single submitter clinical testing
Mendelics RCV000708862 SCV000837876 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160662 SCV000902890 likely benign Hereditary cancer-predisposing syndrome 2016-06-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780471 SCV000917744 likely benign not specified 2019-05-17 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1054G>A (p.Val352Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.4e-05 in 282596 control chromosomes, predominantly at a frequency of 0.00029 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 2 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. The variant, c.1054G>A, has been reported in the literature in individuals affected with breast cancer or colon cancer (Tung_2014, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as likely benign and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000986713 SCV001135802 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000986713 SCV001297401 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656893 SCV001469561 likely benign not provided 2020-08-13 criteria provided, single submitter clinical testing

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