Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001022650 | SCV001184410 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-05-22 | criteria provided, single submitter | clinical testing | The c.453+2_453+7delTAAGAAinsGATC intronic pathogenic mutation is located 2 nucleotides after coding exon 5 in the MLH1 gene. This variant results from a deletion of 6 nucleotides and the insertion of 4 nucleotides at positions c.453+2 to c.453+7. This nucleotide region encompasses the canonical donor site, which is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. This alteration has been detected in colon cancer patients in families meeting Amsterdam criteria and with tumor testing results demonstrating microsatellite instability and loss of MLH1 and PMS2 protein expression (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. As such, this alteration is classified as a disease-causing mutation. |
| Myriad Genetics, |
RCV003455121 | SCV004187179 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-14 | 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. |