ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1897-17C>G (rs2308316)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115469 SCV000149378 likely benign not specified 2018-01-04 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.
PreventionGenetics,PreventionGenetics RCV000679269 SCV000805958 likely benign not provided 2017-01-06 criteria provided, single submitter clinical testing
Mendelics RCV000075410 SCV000838028 likely benign Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000776021 SCV000910586 benign Hereditary cancer-predisposing syndrome 2015-07-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000115469 SCV000917655 likely benign not specified 2018-06-06 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1897-17C>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/5 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 0.00024 in 277094 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (0.00024 vs 0.00071), allowing no conclusion about variant significance. The variant, c.1897-17C>G, has been reported in the literature in individuals affected with Lynch Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome (Berginc_2009, Fearnhead_2004, Kadiyska_2006). Co-occurrences with other pathogenic variants have been reported (MLH1 c.340_341dup, p.Ile115LeufsX22; MLH1 c.340dup, p.Thr114AsnfsX8), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory after 2014 without evidence for independent evaluation classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000987187 SCV001136429 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing

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