ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1410-10T>G

gnomAD frequency: 0.00038  dbSNP: rs372053184
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079322 SCV000284018 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-03 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000580704 SCV000684742 likely benign Hereditary cancer-predisposing syndrome 2015-10-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001818568 SCV000696110 benign not specified 2022-04-06 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1410-10T>G 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. 4/4 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 8.4e-05 in 251424 control chromosomes, predominantly at a frequency of 0.0008 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 1.13 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1410-10T>G has been reported in the literature as a VUS in individuals with colorectal cancer (example, Poynter_2008, Guindalini_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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.
GeneDx RCV000586910 SCV001941704 benign not provided 2015-03-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001818568 SCV002071324 likely benign not specified 2020-02-27 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000580704 SCV002528648 benign Hereditary cancer-predisposing syndrome 2020-10-01 criteria provided, single submitter curation

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