Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Color Diagnostics, |
RCV001176427 | SCV001340404 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-03-25 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with aspartic acid at codon 51 of the MLH1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that this variant causes a significant defect in mismatch repair activity (personal communications with N. de Wind, Leiden University Medical Center and PMID: 30504929). This variant has been reported in an unaffected individual and in this individual's father and paternal grandmother, who are affected with colon, pancreatic, and gastric cancers (PMID: 26380867). This variant has also been reported in an individual affected with Lynch syndrome (PMID: 25430799). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
Myriad Genetics, |
RCV003449577 | SCV004188276 | likely pathogenic | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-07-11 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function. This variant is expected to disrupt protein structure [Myriad internal data]. |
Invitae | RCV003594099 | SCV004293448 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-08-01 | 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. Experimental studies have shown that this missense change affects MLH1 function (PMID: 15475387, 26380867; external communication). 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: 918697). This missense change has been observed in individual(s) with clinical features of Lynch syndrome and/or colon cancer (PMID: 25430799, 26380867; external communication). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 51 of the MLH1 protein (p.Val51Asp). |
Constitutional Genetics Lab, |
RCV001249948 | SCV001423890 | likely pathogenic | Lynch-like syndrome | 2019-07-01 | no assertion criteria provided | clinical testing |