ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1731+5G>A (rs267607850)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075328 SCV000106321 pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Variant causes splicing aberration leading to truncated protein: complete inactivation of variant allele
Invitae RCV001201385 SCV000261840 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-16 criteria provided, single submitter clinical testing This sequence change falls in intron 15 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 been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18561205, 19685281, Invitae). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 18561205, 19685281). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV001012888 SCV001173402 likely pathogenic Hereditary cancer-predisposing syndrome 2018-04-12 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Functionally-validated splicing mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)

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