Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000075771 | SCV000106780 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
Invitae | RCV000550590 | SCV000625179 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-10-28 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 7 and introduces a premature termination codon (PMID: 22949379; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 90282). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 20233461, 21681552, 28874130, 30238922, 34178123; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 7 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. |
A. |
RCV000075771 | SCV000914315 | likely pathogenic | Lynch syndrome | 2019-01-30 | criteria provided, single submitter | research | |
Ambry Genetics | RCV001024637 | SCV001186685 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-08-22 | criteria provided, single submitter | clinical testing | The c.588+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 7 in the MLH1 gene. This nucleotide position is highly conserved in available vertebrate species. This mutation was identified in a Brazilian individual meeting Bethesda or Amsterdam criteria whose tumor demonstrated loss of MLH1 and PMS2 by IHC analysis (Valentin MD et al. Fam. Cancer, 2011 Dec;10:641-7). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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 alteration is classified as a disease-causing mutation. |
Myriad Genetics, |
RCV003452752 | SCV004186040 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-17 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18561205]. |