ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1558+4C>T (rs531873434)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167439 SCV000218295 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000167439 SCV000684753 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-04 criteria provided, single submitter clinical testing
GeneDx RCV000418566 SCV000524498 likely benign not specified 2016-11-14 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.
Invitae RCV000199499 SCV000254353 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-03 criteria provided, single submitter clinical testing This sequence change falls in intron 13 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 187689). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000418566 SCV000601360 uncertain significance not specified 2017-05-29 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000758645 SCV000887406 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.1558+4C>T has a 44.5% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.

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