Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000468232 | SCV000543646 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-08-27 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 203 of the MLH1 protein (p.Asp203His). This variant is not present in population databases (gnomAD no frequency). 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: 405431). 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. |
| Gene |
RCV001764375 | SCV001990343 | uncertain significance | not provided | 2021-07-27 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on 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) |
| Ambry Genetics | RCV003298469 | SCV004006423 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-04 | criteria provided, single submitter | clinical testing | The p.D203H variant (also known as c.607G>C), located in coding exon 8 of the MLH1 gene, results from a G to C substitution at nucleotide position 607. The aspartic acid at codon 203 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| All of Us Research Program, |
RCV004000664 | SCV004832774 | uncertain significance | Lynch syndrome | 2024-02-22 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with histidine at codon 203 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 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. |
| Baylor Genetics | RCV004567957 | SCV005058003 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2024-01-08 | criteria provided, single submitter | clinical testing |