Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075934 | SCV000106951 | pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Multifactorial likelihood analysis posterior probability >0.99 |
| Invitae | RCV000529157 | SCV000625210 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-10-08 | criteria provided, single submitter | clinical testing | Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). ClinVar contains an entry for this variant (Variation ID: 90441). This missense change has been observed in individuals with Lynch syndrome (PMID: 12011148, 21520333, 31857677). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 306 of the MLH1 protein (p.Asn306Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. 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. Experimental studies have shown that this missense change affects MLH1 function (PMID: 30504929). |
| Department of Pediatrics, |
RCV001523813 | SCV001478124 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2020-12-15 | criteria provided, single submitter | research | |
| Ambry Genetics | RCV004019106 | SCV005033352 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-20 | criteria provided, single submitter | clinical testing | The p.N306K variant (also known as c.918T>A), located in coding exon 11 of the MLH1 gene, results from a T to A substitution at nucleotide position 918. The asparagine at codon 306 is replaced by lysine, an amino acid with similar properties. In an in vitro complementation assay, this variant was determined to be functionally deficient (Drost M et al. Genet Med, 2019 Jul;21:1486-1496). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |