Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000708243 | SCV000837353 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2018-02-21 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exon 19 of the MLH1 gene. The 5' boundary is likely confined to intron 18. 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 protein product or disrupt mRNA translation. Deletions of exon 19 has been reported in individuals affected with Lynch syndrome (PMID: 23354634). ClinVar contains an entry for deletions of exon 19 (Variation ID: 90057). This deletion eliminates amino acids 702-756 of the MLH1 protein and affects the highly conserved C-terminal domain responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). Truncating variants downstream of this variant (including p.Lys732* and p.Tyr750*) have been reported in individuals affected with Lynch syndrome and have been determined to be pathogenic (PMID: 10923051, 25197397, 10422993, Invitae). This suggests that disruption of this region of the MLH1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. |