Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000568925 | SCV000669550 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-08-22 | criteria provided, single submitter | clinical testing | The p.R18G variant (also known as c.52C>G), located in coding exon 1 of the MLH1 gene, results from a C to G substitution at nucleotide position 52. The arginine at codon 18 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly 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. |
Invitae | RCV000685595 | SCV000813080 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-01-26 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs367654552, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 18 of the MLH1 protein (p.Arg18Gly). This missense change has been observed in individual(s) with breast cancer (PMID: 32601921). 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 expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 483546). |
Illumina Laboratory Services, |
RCV001147829 | SCV001308680 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
All of Us Research Program, |
RCV004001025 | SCV004835222 | uncertain significance | Lynch syndrome | 2023-05-16 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with glycine at codon 18 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 been identified in 1/251420 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. |