Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000470621 | SCV000543629 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-13 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 384 of the MLH1 protein (p.Val384Ile). This variant is present in population databases (rs757350157, gnomAD 0.0009%). 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: 405421). 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. |
| Ambry Genetics | RCV002348276 | SCV002621453 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-08 | criteria provided, single submitter | clinical testing | The p.V384I variant (also known as c.1150G>A), located in coding exon 12 of the MLH1 gene, results from a G to A substitution at nucleotide position 1150. The valine at codon 384 is replaced by isoleucine, 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. |
| Johns Hopkins Genomics, |
RCV003150815 | SCV003839109 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2022-12-14 | criteria provided, single submitter | clinical testing | This MLH1 missense variant (rs757350157) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 1/151552 total alleles; 0.00066%; no homozygotes). It has been reported in ClinVar (Variation ID 405421), but has not been reported in the literature, to our knowledge. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the other predicts that it would be tolerated, and the valine residue at this position is evolutionarily conserved across all of the species assessed. We consider the clinical significance of c.1150G>A; p.Val384Ile in MLH1 to be uncertain at this time. |
| Johns Hopkins Genomics, |
RCV003150814 | SCV003839110 | uncertain significance | Mismatch repair cancer syndrome 1 | 2022-12-14 | criteria provided, single submitter | clinical testing | This MLH1 missense variant (rs757350157) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 1/151552 total alleles; 0.00066%; no homozygotes). It has been reported in ClinVar (Variation ID 405421), but has not been reported in the literature, to our knowledge. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the other predicts that it would be tolerated, and the valine residue at this position is evolutionarily conserved across all of the species assessed. We consider the clinical significance of c.1150G>A; p.Val384Ile in MLH1 to be uncertain at this time. |
| All of Us Research Program, |
RCV004000659 | SCV004826248 | uncertain significance | Lynch syndrome | 2023-10-27 | criteria provided, single submitter | clinical testing |