ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2103+1G>C (rs267607888)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075530 SCV000106527 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV001380414 SCV001578479 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-02-19 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 18) of the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with MLH1-related conditions (PMID: 27247567, 8571956, 22883484, 28195393, 15342696). ClinVar contains an entry for this variant (Variation ID: 90045). 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 may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the C-terminus of the MLH1 protein. Other variant(s) that disrupt this region (p.Trp714*) have been determined to be pathogenic (PMID: 8863153, 9697702, 17510385, 12810663, 12799449, 16338176, 20533529). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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