Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000781989 | SCV000920445 | likely pathogenic | Lynch syndrome | 2018-12-19 | reviewed by expert panel | curation | Multifactorial likelihood analysis posterior probability > 0.95 (0.966) |
| Invitae | RCV000696093 | SCV000824640 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-06-27 | criteria provided, single submitter | clinical testing | 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. ClinVar contains an entry for this variant (Variation ID: 574220). This missense change has been observed in individuals with Lynch syndrome (Invitae; external communication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 147 of the MLH1 protein (p.Gly147Glu). |
| Ambry Genetics | RCV002332456 | SCV002627993 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-11-04 | criteria provided, single submitter | clinical testing | The p.G147E variant (also known as c.440G>A), located in coding exon 5 of the MLH1 gene, results from a G to A substitution at nucleotide position 440. The glycine at codon 147 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. This variant has been identified as germline in an individual meeting Amsterdam criteria with MSI-H colorectal cancer also demonstrating loss of PMS2 and weak MLH1 staining by IHC. Somatic copy-neutral loss of heterozygosity (CN-LOH) of MLH1 was also identified in this individual's tumor (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been classified as likely pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |