ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1665T>C (p.Leu555=) (rs749204990)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167487 SCV000218345 likely benign Hereditary cancer-predisposing syndrome 2014-12-29 criteria provided, single submitter clinical testing
Color RCV000167487 SCV000684763 likely benign Hereditary cancer-predisposing syndrome 2017-06-05 criteria provided, single submitter clinical testing
GeneDx RCV000436812 SCV000513628 likely benign not specified 2017-10-24 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 RCV000436812 SCV000919659 uncertain significance not specified 2018-08-30 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1665T>C (p.Leu555Leu) 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 8.1e-06 in 246016 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1665T>C 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 VUS-possibly benign.
Invitae RCV000560071 SCV000625088 likely benign Hereditary nonpolyposis colon cancer 2017-06-30 criteria provided, single submitter clinical testing

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