ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1990-6G>A (rs117221851)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226567 SCV000284042 likely benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000430988 SCV000513631 likely benign not specified 2017-09-19 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color RCV000580651 SCV000684788 likely benign Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing
Counsyl RCV000663093 SCV000786196 uncertain significance Lynch syndrome II 2018-03-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000430988 SCV000919644 likely benign not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1990-6G>A 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 6.4e-05 in 250998 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1990-6G>A has been reported in the literature in four Japanese individuals affected with colorectal cancer, however two tumors from these patients were analyzed and found to exhibit microsatellite stability and expression of all MMR proteins (Kiyozumi_2019). This report therefore does not support an association of the variant with Lynch Syndrome. Furthermore, co-occurrence with another pathogenic variant has been reported [APC c.3184_3187delCAAA (p.Gln1062ValfsX63) in an internal LCA sample], providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three laboratories classified the variant as likely benign, while one laboratory classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000663093 SCV001136432 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing

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