Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000221354 | SCV000274768 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-22 | criteria provided, single submitter | clinical testing | The p.E613D variant (also known as c.1839G>T), located in coding exon 16 of the MLH1 gene, results from a G to T substitution at nucleotide position 1839. The glutamic acid at codon 613 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well 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. |
| ARUP Laboratories, |
RCV001000927 | SCV001158019 | uncertain significance | not specified | 2018-12-18 | criteria provided, single submitter | clinical testing | The MLH1 c.1839G>T; p.Glu613Asp variant (rs876658919), to our knowledge, is not reported in the medical literature but is reported as uncertain in ClinVar (Variation ID: 231039). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glutamate at codon 613 is weakly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Glu613Asp variant is uncertain at this time. |
| Invitae | RCV001350153 | SCV001544533 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-05-27 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 231039). 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 glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 613 of the MLH1 protein (p.Glu613Asp). |
| All of Us Research Program, |
RCV003997879 | SCV004843222 | uncertain significance | Lynch syndrome | 2023-11-30 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with aspartic acid at codon 613 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 hereditary cancer 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. |