Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000218037 | SCV000275866 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-02-19 | criteria provided, single submitter | clinical testing | Insufficient or Conflicting Evidence |
Gene |
RCV000480533 | SCV000571659 | uncertain significance | not provided | 2018-02-15 | criteria provided, single submitter | clinical testing | This variant is denoted MLH1 c.1460G>A at the cDNA level, p.Arg487Gln (R487Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Arg487Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). MLH1 Arg487Gln is located in the region of interaction with EXO1 (Andersen 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Arg487Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Invitae | RCV000630048 | SCV000751004 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2019-12-05 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glutamine at codon 487 of the MLH1 protein (p.Arg487Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587778917, ExAC 0.03%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 89745). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. |
Color | RCV000218037 | SCV000903938 | likely benign | Hereditary cancer-predisposing syndrome | 2016-10-16 | criteria provided, single submitter | clinical testing | |
Division of Medical Genetics, |
RCV001257464 | SCV001434264 | uncertain significance | Lynch syndrome II | 2020-05-05 | criteria provided, single submitter | clinical testing | To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.00004242 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses predict that this variant may not alter protein structure/function. At this time, it is unknown whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance. BP4 |