Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001033451 | SCV001196758 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-01-03 | criteria provided, single submitter | clinical testing | This variant results in a copy number gain of the genomic region encompassing exons 17-18 and part of exon 19 of the MLH1 gene. Three copies of exon 17-18 and four copies of exon 19 (i.e., a triplication) have been detected and are likely in tandem. This variant would be expected to be in-frame, preserving the integrity of the reading frame. A similar gain has not been reported in the literature in individuals with MLH1-related conditions. This variant disrupts the C-terminal PMS2 interaction domain of the MLH1 protein, which is necessary for proper MLH1-PMS2 dimerization and normal protein functioning (PMID: 10037723, 11793442, 16083711). While functional studies have not been performed to directly test the effect of this variant on MLH1 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |