ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.116+8G>A (rs904872305)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431627 SCV000530359 likely benign not specified 2016-07-26 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 RCV000431627 SCV000919649 uncertain significance not specified 2018-06-04 criteria provided, single submitter clinical testing Variant summary: MLH1 c.116+8G>A alters a 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 was absent in 244694 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.116+8G>A, has been reported in the literature in a family that did not fulfill Amsterdam criteria (Pastrello_2011). This report does 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. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000471339 SCV000555958 likely benign Lynch syndrome 2016-08-22 criteria provided, single submitter clinical testing

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