Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000707997 | SCV000837107 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2019-07-02 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 16-19 of the MLH1 gene. The 5' boundary is likely confined to intron 15. The 3' end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated MLH1 protein. A similar deletion has been observed in 7 unrelated individuals affected with Lynch syndrome, colon cancer and/or sebaceous skin cancer (PMID: 14635101, 16143124, 15713769). ClinVar contains an entry for this variant (Variation ID: 89865). This deletion is expected to remove the most C-terminal 179 amino acids (Glu578-Cys756) from the MLH1 protein. This region includes most of the PMS2 interaction domain, which is necessary for MLH1-PMS2 dimerization and normal protein functioning (PMID: 10037723, 11292842, 20533529). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic. |