Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV004943930 | SCV005451103 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-10-29 | criteria provided, single submitter | clinical testing | The p.G1316R pathogenic mutation (also known as c.3946G>A), located in coding exon 9 of the MSH6 gene, results from a G to A substitution at nucleotide position 3946. The glycine at codon 1316 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in the homozygous state in an individual who met clinical criteria for MSH6-related constitutional mismatch repair deficiency (Bakry D et al. Eur J Cancer, 2014 Mar;50:987-96; Shuen AY et al. J Clin Oncol, 2019 Feb;37:461-470). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004999547 | SCV005623500 | uncertain significance | not provided | 2024-08-01 | criteria provided, single submitter | clinical testing | The MSH6 c.3946G>A (p.Gly1316Arg) variant has been reported in the published literature in a homozygous state in an individual with Constitutional mismatch repair deficiency (CMMRD) (PMID: 24440087 (2014)). The frequency of this variant in the general population, 0.000004 (1/249530 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |
| Department of Pathology and Laboratory Medicine, |
RCV000501588 | SCV000592663 | uncertain significance | Carcinoma of colon | no assertion criteria provided | clinical testing | The p.Gly1316Arg variant has not been reported in the literature nor previously identified by our laboratory. The p.Gly1316 residue is conserved in mammals, but not in lower organisms such as invertebrates. Computational analyses including PolyPhen2 and SIFT suggest the variant may impact the protein product. However, AlignGVGD predicts a more benign role for the variant. However, these prediction tools are not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. |