ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
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.
Integrated Genetics/Laboratory Corporation of America RCV000430988 SCV000919644 likely benign not specified 2018-05-18 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 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.1990-6G>A in individuals affected with 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 evidence outlined above, the variant was classified as likely benign.
Invitae RCV000226567 SCV000284042 likely benign Hereditary nonpolyposis colon cancer 2017-12-29 criteria provided, single submitter clinical testing

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