Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
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 | 2022-06-15 | criteria provided, single submitter | clinical testing | 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. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 90045). Disruption of this splice site has been observed in individual(s) with MLH1-related conditions (PMID: 8571956, 15342696, 22883484, 27247567, 28195393). This variant is not present in population databases (gnomAD no frequency). 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. |