Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000566506 | SCV000675047 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-02-25 | criteria provided, single submitter | clinical testing | The p.M47V variant (also known as c.139A>G), located in coding exon 2 of the SDHAF2 gene, results from an A to G substitution at nucleotide position 139. The methionine at codon 47 is replaced by valine, an amino acid with highly similar properties. This alteration was detected in 1/443 patients with apparently sporadic paragangliomas or pheochromocytomas and 0/200 healthy blood donors; however, authors of this study concluded that this alteration was non-pathogenic (Bayley JP et al. Lancet Oncol. 2010 Apr;11:366-72). This alteration was also identified in a Spanish family suspicious of hereditary breast and/or ovarian cancer syndrome (Bonache S et al. J Cancer Res Clin Oncol, 2018 Dec;144:2495-2513). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000703323 | SCV000832220 | uncertain significance | Hereditary pheochromocytoma-paraganglioma | 2024-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 47 of the SDHAF2 protein (p.Met47Val). This variant is present in population databases (rs111402137, gnomAD 0.009%). This missense change has been observed in individual(s) with phaeochromocytoma (PMID: 20071235). ClinVar contains an entry for this variant (Variation ID: 486407). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. |
| Baylor Genetics | RCV003471907 | SCV004202927 | uncertain significance | Paragangliomas 2 | 2024-03-21 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003478296 | SCV004220247 | uncertain significance | not provided | 2023-01-19 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population, 0.000028 (8/282814 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in one individual with phaeochromocytoma (PMID: 20071235 (2010)), and in a family clinically suspicious of hereditary breast/ovarian cancer (PMID: 30306255 (2018)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. |
| All of Us Research Program, |
RCV000703323 | SCV004821402 | uncertain significance | Hereditary pheochromocytoma-paraganglioma | 2023-08-15 | criteria provided, single submitter | clinical testing |