Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001045293 | SCV001209134 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2019-03-02 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). Variants that disrupt this acceptor splice site have been observed in several individuals affected with Lynch syndrome, and have been reported to segregate with disease in a family (PMID: 26248088, 28944238, 8971183, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 4 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
Color Diagnostics, |
RCV003584807 | SCV004359180 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-12-06 | criteria provided, single submitter | clinical testing | This variant causes an A to T nucleotide substitution at the -2 position of intron 4 of the MLH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with hereditary cancer in the literature. Another variant at this site (c.381-2A>G) has been reported in individuals affected with Lynch syndrome (ClinVar ID: 90195). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |