Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000074854 | SCV000108066 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
Ambry Genetics | RCV002453381 | SCV002615189 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-04-27 | criteria provided, single submitter | clinical testing | The c.3438+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 5 of the MSH6 gene. This variant has been reported in an individual with MSI-H rectal cancer diagnosed at age 45 and meeting Amsterdam criteria. It was also reported in an individual diagnosed with MSI-H colon cancer at ag 43, ovarian cancer at age 43, and endometrial cancer at age 53 (Overbeek LI et al. Br J Cancer, 2007 May;96:1605-12). This variant was shown by minigene assay to result in out of frame skipping of exon 5 (van der Klift HM et al. Mol Genet Genomic Med, 2015 Jul;3:327-45). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Myriad Genetics, |
RCV003450967 | SCV004189274 | likely pathogenic | Lynch syndrome 5 | 2023-08-23 | criteria provided, single submitter | clinical testing | This variant is considered likely 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. |