Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001014880 | SCV001175646 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-11-01 | criteria provided, single submitter | clinical testing | The p.I75V variant (also known as c.223A>G), located in coding exon 3 of the MLH1 gene, results from an A to G substitution at nucleotide position 223. The isoleucine at codon 75 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly 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. |
| Labcorp Genetics |
RCV001234162 | SCV001406793 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-06-04 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 75 of the MLH1 protein (p.Ile75Val). 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: 820939). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. |
| Neuberg Centre For Genomic Medicine, |
RCV004720289 | SCV005329323 | uncertain significance | Muir-Torré syndrome | 2023-05-20 | criteria provided, single submitter | clinical testing | The observed missense c.223A>G(p.Ile75Val) variant in MLH1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ile75Val variant is absent in gnomAD Exomes database. This variant has been submitted to the ClinVar database as Uncertain significance. The amino acid change p.Ile75Val in MLH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ile at position 75 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. Multiple line of computational evidence (Polyphen - probably Damaging, SIFT - Damaging, and MutationTaster - disease causing) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). |