Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000230665 | SCV000284032 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-12-15 | 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. 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. ClinVar contains an entry for this variant (Variation ID: 237321). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 584 of the MLH1 protein (p.Asp584Glu). |
Ambry Genetics | RCV000576092 | SCV000662058 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-16 | criteria provided, single submitter | clinical testing | The p.D584E variant (also known as c.1752C>G), located in coding exon 16 of the MLH1 gene, results from a C to G substitution at nucleotide position 1752. The aspartic acid at codon 584 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is not well 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. |
Gene |
RCV003227725 | SCV003925013 | uncertain significance | not provided | 2023-04-27 | 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) |
All of Us Research Program, |
RCV003998740 | SCV004832739 | uncertain significance | Lynch syndrome | 2023-06-26 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with glutamic acid at codon 584 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/251270 chromosomes 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. |