Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001179197 | SCV001343808 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-05-07 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001875924 | SCV002299835 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2021-05-18 | criteria provided, single submitter | clinical testing | 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. This variant disrupts the p.Leu574 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7757073, 15365995, 21404117, 23403630, 10037723, 9697702, 17510385). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 920440). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 574 of the MLH1 protein (p.Leu574Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. |
| Ambry Genetics | RCV001179197 | SCV002714177 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-05-27 | criteria provided, single submitter | clinical testing | The p.L574V variant (also known as c.1720C>G), located in coding exon 15 of the MLH1 gene, results from a C to G substitution at nucleotide position 1720. The leucine at codon 574 is replaced by valine, an amino acid with highly similar properties. 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. |