Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001235792 | SCV001408497 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-07-08 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 696 of the MLH1 protein (p.Thr696Asn). 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: 962013). 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 not expected to disrupt 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. |
KCCC/NGS Laboratory, |
RCV003448380 | SCV004174870 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine with asparagine at codon 696 of the MLH1 protein (p.Thr696Asn). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Therefore, it has been classified as a Variant of Uncertain Significance. |