Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001038237 | SCV001201700 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2020-03-18 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MLH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with serine at codon 166 of the MLH1 protein (p.Leu166Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine. |
| Gene |
RCV001759733 | SCV001996925 | uncertain significance | not provided | 2019-11-07 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect |
| Ambry Genetics | RCV002337105 | SCV002642197 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-10-04 | criteria provided, single submitter | clinical testing | The p.L166S variant (also known as c.497T>C), located in coding exon 6 of the MLH1 gene, results from a T to C substitution at nucleotide position 497. The leucine at codon 166 is replaced by serine, an amino acid with dissimilar 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 0.002% (greater than 65000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.L166S remains unclear. |