Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000773778 | SCV000907478 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-05 | criteria provided, single submitter | clinical testing | This missense variant replaces alanine with aspartic acid at codon 442 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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. |
| Labcorp Genetics |
RCV000811634 | SCV000951909 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 442 of the MLH1 protein (p.Ala442Asp). 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: 629089). 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 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. |
| Sema4, |
RCV000773778 | SCV002528639 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-19 | criteria provided, single submitter | curation | |
| Ambry Genetics | RCV000773778 | SCV002692985 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-10-29 | criteria provided, single submitter | clinical testing | The p.A442D variant (also known as c.1325C>A), located in coding exon 12 of the MLH1 gene, results from a C to A substitution at nucleotide position 1325. The alanine at codon 442 is replaced by aspartic acid, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV003465695 | SCV004190627 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-08-31 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV004807142 | SCV005427878 | uncertain significance | Lynch syndrome | 2024-05-17 | criteria provided, single submitter | clinical testing |