Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002446974 | SCV002753611 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-10-29 | criteria provided, single submitter | clinical testing | The c.306+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 3 in the MLH1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Department of Pathology and Laboratory Medicine, |
RCV000499634 | SCV000592350 | pathogenic | Carcinoma of colon | no assertion criteria provided | clinical testing | The c.306+2T>G variant has not been previously reported in the literature. The variant is located in the 5' splice region, and is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant +1 and +2 positions of the splice consensus sequence. Consensus splice site variants of the MLH1 gene are a known disease mechanism and is expected to cause Lynch syndrome. In summary, based on above information, this variant is classified as pathogenic. |