Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV001181960 | SCV001347225 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-11-20 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with methionine at codon 425 of the MLH1 protein. Computational prediction tool 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). 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. |
Invitae | RCV001876048 | SCV002269976 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2021-10-23 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, a(n) basic and polar amino acid, with methionine, a(n) neutral and non-polar amino acid, at codon 425 of the MLH1 protein (p.Arg425Met). 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: 922102). 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. 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 | RCV001181960 | SCV002687604 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-11-11 | criteria provided, single submitter | clinical testing | The p.R425M variant (also known as c.1274G>T), located in coding exon 12 of the MLH1 gene, results from a G to T substitution at nucleotide position 1274. The arginine at codon 425 is replaced by methionine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |