Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001069082 | SCV001234228 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-01-13 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ala21 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14961575, 21404117, 30013564). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 862374). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 21 of the MLH1 protein (p.Ala21Ser). |
| Ambry Genetics | RCV002355096 | SCV002655059 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-18 | criteria provided, single submitter | clinical testing | The p.A21S variant (also known as c.61G>T), located in coding exon 1 of the MLH1 gene, results from a G to T substitution at nucleotide position 61. The alanine at codon 21 is replaced by serine, an amino acid with similar 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. |
| All of Us Research Program, |
RCV004000181 | SCV004835226 | uncertain significance | Lynch syndrome | 2023-06-15 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with serine at codon 21 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 hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.62C>A (p.Ala21Glu), c.62C>T (p.Ala21Val), c.61G>C (p.Ala21Pro) are considered to be disease-causing (ClinVar variation ID: 90297, 90298, 1511560), suggesting that this position is important for the protein function. 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. |