Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000767137 | SCV000572582 | uncertain significance | not provided | 2022-07-01 | 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; This variant is associated with the following publications: (PMID: 24728327, 22753075) |
| Ambry Genetics | RCV000571271 | SCV000662060 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-02-28 | criteria provided, single submitter | clinical testing | The p.K241E variant (also known as c.721A>G), located in coding exon 9 of the MLH1 gene, results from an A to G substitution at nucleotide position 721. The lysine at codon 241 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. 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. |
| Counsyl | RCV000662556 | SCV000785146 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2017-05-12 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000694594 | SCV000823045 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 241 of the MLH1 protein (p.Lys241Glu). 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: 134657). 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. |
| Myriad Genetics, |
RCV000662556 | SCV004018155 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-03-14 | criteria provided, single submitter | clinical testing | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. |
| All of Us Research Program, |
RCV003997345 | SCV004840899 | uncertain significance | Lynch syndrome | 2023-12-01 | criteria provided, single submitter | clinical testing | This missense variant replaces lysine with glutamic acid at codon 241 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. |
| ITMI | RCV000121358 | SCV000085538 | not provided | not specified | 2013-09-19 | no assertion provided | reference population |