Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001059938 | SCV001224593 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-11-02 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 691 of the MLH1 protein (p.Ile691Leu). 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: 854812). 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 with a negative predictive value of 95%. 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. |
Color Diagnostics, |
RCV001806005 | SCV002052474 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-27 | criteria provided, single submitter | clinical testing | This missense variant replaces isoleucine with leucine at codon 691 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. |
Ambry Genetics | RCV001806005 | SCV002729773 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-07 | criteria provided, single submitter | clinical testing | The p.I691L variant (also known as c.2071A>C), located in coding exon 18 of the MLH1 gene, results from an A to C substitution at nucleotide position 2071. The isoleucine at codon 691 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |