Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000680200 | SCV000807664 | likely pathogenic | Lynch syndrome 1 | 2018-06-13 | reviewed by expert panel | curation | Multifactorial likelihood analysis posterior probability > 0.99 (0.998) |
| Labcorp Genetics |
RCV001861879 | SCV002269197 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-03-11 | criteria provided, single submitter | clinical testing | Experimental studies have shown that this missense change affects MLH1 function (PMID: 32849802). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 308 of the MLH1 protein (p.His308Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 32849802). ClinVar contains an entry for this variant (Variation ID: 561172). |
| Ambry Genetics | RCV002369811 | SCV002688177 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-16 | criteria provided, single submitter | clinical testing | The p.H308P variant (also known as c.923A>C), located in coding exon 11 of the MLH1 gene, results from an A to C substitution at nucleotide position 923. The histidine at codon 308 is replaced by proline, an amino acid with similar properties. This alteration was identified in an individual diagnosed with colorectal cancer that was MSI-H with no loss of MMR protein expression by IHC (Poynter JN et al. Cancer Epidemiol Biomarkers Prev, 2008 Nov;17:3208-15). This alteration was also reported in a cohort study of 1231 colorectal cancer (CRC) cases selected from the Colon Cancer Family Registry for mutation screening and 93 individuals without CRC from among the spouses of cases served as controls (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). In a cell-free in vitro MMR activity (CIMRA) assay, this variant demonstrated reduced mismatch repair activity (Thompson BA et al. Front Genet, 2020 Jul;11:798). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |