Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| University of Washington Department of Laboratory Medicine, |
RCV000758634 | SCV000887391 | pathogenic | Lynch syndrome | 2018-05-01 | criteria provided, single submitter | clinical testing | MLH1 NM_000249.3:c.100G>A has a 99.6% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214. |
| Ambry Genetics | RCV001016980 | SCV001177996 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-08-23 | criteria provided, single submitter | clinical testing | The p.E34K variant (also known as c.100G>A), located in coding exon 1 of the MLH1 gene, results from a G to A substitution at nucleotide position 100. The glutamic acid at codon 34 is replaced by lysine, an amino acid with similar properties. This variant was identified in a proband whose colorectal tumor was microsatellite stable (Ambry internal data). This variant was also identified as somatic in conjunction with MLH1 LOH in a colorectal cancer that demonstrated high microsatellite instability, but had normal expression of the mismatch repair proteins on immunohistochemistry (Pearlman R et al. J Med Genet, 2019 Jul;56:462-470; Chen W et al. Hum Pathol, 2020 Sep;103:34-41). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV003594028 | SCV004367109 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-12-28 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 34 of the MLH1 protein (p.Glu34Lys). 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: 619551). 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 expected to disrupt MLH1 protein function with a positive 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. |