Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000214352 | SCV000279669 | uncertain significance | not provided | 2015-12-06 | criteria provided, single submitter | clinical testing | This variant is denoted MLH1 c.2089C>G at the cDNA level, p.Leu697Val (L697V) at the protein level, and results in the change of a Leucine to a Valine (CTC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Leu697Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. MLH1 Leu697Val occurs at a position that is conserved through mammals and is located in the Pms1p-interactive domain and region of interaction with PMS2, MLH3, and PMS1 (Pang 1997, Raevaara 2005). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Leu697Val is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Color Diagnostics, |
RCV000579797 | SCV000684798 | uncertain significance | Hereditary cancer-predisposing syndrome | 2018-08-18 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000800252 | SCV000939953 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-10-17 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 697 of the MLH1 protein (p.Leu697Val). 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: 234666). 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. |
| Ambry Genetics | RCV000579797 | SCV001175089 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-16 | criteria provided, single submitter | clinical testing | The p.L697V variant (also known as c.2089C>G), located in coding exon 18 of the MLH1 gene, results from a C to G substitution at nucleotide position 2089. The leucine at codon 697 is replaced by valine, 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. |
| All of Us Research Program, |
RCV003998637 | SCV004843275 | uncertain significance | Lynch syndrome | 2023-08-08 | criteria provided, single submitter | clinical testing |