ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.589-8T>C (rs1017112753)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001703603 SCV000518765 likely benign not provided 2018-10-18 criteria provided, single submitter clinical testing
Invitae RCV000465259 SCV000555966 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000582031 SCV000689898 likely benign Hereditary cancer-predisposing syndrome 2017-07-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000421345 SCV000696172 likely benign not specified 2021-07-05 criteria provided, single submitter clinical testing Variant summary: MLH1 c.589-8T>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 4e-06 in 251330 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.589-8T>C in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/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 likely benign. Based on the emerging peer consensus and the evidence outlined above, the variant was re-classified as likely benign.

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