Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000567252 | SCV000662068 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-03-27 | criteria provided, single submitter | clinical testing | The p.I643T variant (also known as c.1928T>C), located in coding exon 17 of the MLH1 gene, results from a T to C substitution at nucleotide position 1928. The isoleucine at codon 643 is replaced by threonine, 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 alteration remains unclear. |
| Labcorp Genetics |
RCV001295869 | SCV001484820 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-09-26 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 643 of the MLH1 protein (p.Ile643Thr). 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: 479679). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. |
| Gene |
RCV001764638 | SCV002000355 | uncertain significance | not provided | 2020-11-24 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
| Baylor Genetics | RCV003470819 | SCV004193005 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-05-16 | criteria provided, single submitter | clinical testing |