ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2103+1G>C

dbSNP: 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
Labcorp Genetics (formerly Invitae), Labcorp RCV001380414 SCV001578479 pathogenic Hereditary nonpolyposis colorectal neoplasms 2025-01-22 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 18 of the MLH1 gene. While this variant 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 (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with MLH1-related conditions (PMID: 8571956, 15342696, 22883484, 27247567, 28195393). ClinVar contains an entry for this variant (Variation ID: 90045). Variants that disrupt 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. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Trp714*) have been determined to be pathogenic (PMID: 8863153, 9697702, 12799449, 12810663, 16338176, 17510385, 20533529). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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