Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001058153 | SCV001222700 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 587 of the MLH1 protein (p.Met587Ile). This variant is present in population databases (rs747665234, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 853362). 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 not expected to disrupt MLH1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV002402421 | SCV002711738 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-06-16 | criteria provided, single submitter | clinical testing | The p.M587I variant (also known as c.1761G>A), located in coding exon 16 of the MLH1 gene, results from a G to A substitution at nucleotide position 1761. The methionine at codon 587 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Baylor Genetics | RCV003462572 | SCV004195101 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-09-21 | criteria provided, single submitter | clinical testing |