ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1731+2T>C

dbSNP: rs267607856
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000550081 SCV000625093 pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-10-28 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 15 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 455399). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 17054581; Invitae). This variant is not present in population databases (gnomAD no frequency).
University of Washington Department of Laboratory Medicine, University of Washington RCV000758580 SCV000887325 pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MLH1 NM_000249.3:c.1731+2T>C has a 99.9% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics RCV002413436 SCV002715677 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-25 criteria provided, single submitter clinical testing The c.1731+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 15 in the MLH1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this variant is classified as likely pathogenic.

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