Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001043115 | SCV001206830 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 46 of the MLH1 protein (p.Ser46Gly). This variant is present in population databases (rs771649701, gnomAD 0.006%). 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: 840987). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MLH1 function with a negative predictive value of 80%. 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 | RCV002379510 | SCV002701204 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-10-02 | criteria provided, single submitter | clinical testing | The p.S46G variant (also known as c.136A>G), located in coding exon 2 of the MLH1 gene, results from an A to G substitution at nucleotide position 136. The serine at codon 46 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well 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. |
| All of Us Research Program, |
RCV004004762 | SCV004835240 | uncertain significance | Lynch syndrome | 2023-11-30 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with glycine at codon 46 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 hereditary cancer in the literature. This variant has been identified in 1/251452 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004998594 | SCV005623549 | uncertain significance | not provided | 2023-11-20 | criteria provided, single submitter | clinical testing | The MLH1 c.136A>G (p.Ser46Gly) variant has not been reported in individuals with MLH1-related conditions in the published literature. The frequency of this variant in the general population, 0.000004 (1/251452 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on MLH1 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant. |