Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000571015 | SCV000662109 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-05-17 | criteria provided, single submitter | clinical testing | The p.Q149H variant (also known as c.447G>C), located in coding exon 5 of the MLH1 gene, results from a G to C substitution at nucleotide position 447. The glutamine at codon 149 is replaced by histidine, an amino acid with highly similar properties. This alteration was detected in one individual, diagnosed with colon cancer at age 34, whose tumor demonstrated absence of the MLH1 protein and negative MLH1 promoter methylation (Ewald J et al. Br J Surg, 2007 Aug;94:1020-7). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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. |
| Invitae | RCV000801416 | SCV000941190 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-10-06 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 149 of the MLH1 protein (p.Gln149His). This variant is present in population databases (rs63750638, gnomAD 0.006%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 17440950). ClinVar contains an entry for this variant (Variation ID: 90220). 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. |
| All of Us Research Program, |
RCV003997130 | SCV004839336 | uncertain significance | Lynch syndrome | 2023-12-01 | criteria provided, single submitter | clinical testing |