Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000460685 | SCV000543639 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-08-31 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 580 of the MLH1 protein (p.Ala580Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MLH1-related conditions (PMID: 37306523). ClinVar contains an entry for this variant (Variation ID: 405428). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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 | RCV000562993 | SCV000673830 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-06-07 | criteria provided, single submitter | clinical testing | The p.A580T variant (also known as c.1738G>A), located in coding exon 16 of the MLH1 gene, results from a G to A substitution at nucleotide position 1738. The alanine at codon 580 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |
| Color Diagnostics, |
RCV000562993 | SCV001359797 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-10-15 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with threonine at codon 580 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Gene |
RCV003156241 | SCV003845745 | uncertain significance | not provided | 2022-09-22 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075, 12799449, 20533529) |
| Department of Pathology and Laboratory Medicine, |
RCV005398571 | SCV006055773 | uncertain significance | Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 | 2022-04-12 | criteria provided, single submitter | clinical testing |