ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.306+3A>G (rs267607731)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000580041 SCV000684816 likely benign Hereditary cancer-predisposing syndrome 2016-06-27 criteria provided, single submitter clinical testing
GeneDx RCV000433858 SCV000528235 likely benign not specified 2018-03-06 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 RCV000557091 SCV000625144 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-31 criteria provided, single submitter clinical testing This sequence change falls in intron 3 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 a MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 386528). Nucleotide substitutions within the consensus splice site are relatively common causes 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, this variant has uncertain impact on MLH1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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