Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000218612 | SCV000279536 | uncertain significance | not provided | 2019-11-04 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with cancer (Li 2019); This variant is associated with the following publications: (PMID: 31391288) |
| Ambry Genetics | RCV000564635 | SCV000673836 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-07-21 | criteria provided, single submitter | clinical testing | The p.K57Q variant (also known as c.169A>C), located in coding exon 2 of the MLH1 gene, results from an A to C substitution at nucleotide position 169. The lysine at codon 57 is replaced by glutamine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001854738 | SCV002144832 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-03-18 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 234589). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs63750877, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 57 of the MLH1 protein (p.Lys57Gln). |
| All of Us Research Program, |
RCV003998632 | SCV004822764 | uncertain significance | Lynch syndrome | 2022-11-28 | criteria provided, single submitter | clinical testing |