Total submissions: 13
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000231407 | SCV000287762 | uncertain significance | Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma | 2025-01-23 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 60 of the SDHB protein (p.Thr60Ala). This variant is present in population databases (rs34599281, gnomAD 0.01%). This missense change has been observed in individual(s) with adenocortical carcinoma and/or thyroid cancer (PMID: 25694510, 28819017). ClinVar contains an entry for this variant (Variation ID: 239423). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SDHB protein function with a negative predictive value of 80%. 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. |
Ambry Genetics | RCV000568901 | SCV000664615 | likely benign | Hereditary cancer-predisposing syndrome | 2019-01-31 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Genomic Research Center, |
RCV000626075 | SCV000746699 | uncertain significance | Gastrointestinal stromal tumor | 2017-12-18 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
RCV001095844 | SCV001252021 | benign | Hereditary pheochromocytoma-paraganglioma | 2017-04-28 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. |
Illumina Laboratory Services, |
RCV001100086 | SCV001256587 | benign | Carney-Stratakis syndrome | 2017-04-28 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. |
Baylor Genetics | RCV001294008 | SCV001482759 | uncertain significance | Paragangliomas 4 | 2019-10-11 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |
Gene |
RCV001563210 | SCV001786112 | uncertain significance | not provided | 2024-08-01 | criteria provided, single submitter | clinical testing | Observed in individuals with pheochromocytoma/paraganglioma, breast cancer, or other cancer (PMID: 25694510, 28873162, 30086788, 34271781, 34906457); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25694510, 28873162, 30086788, 29510530, 28819017, 34426522, 34271781, 34326862, 34906457, 38473309, 30476936) |
Sema4, |
RCV000568901 | SCV002527062 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-05-26 | criteria provided, single submitter | curation | |
Center for Genomic Medicine, |
RCV002465589 | SCV002760645 | uncertain significance | not specified | 2025-03-04 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV000626075 | SCV005056626 | uncertain significance | Gastrointestinal stromal tumor | 2024-03-06 | criteria provided, single submitter | clinical testing | |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001563210 | SCV005624021 | uncertain significance | not provided | 2024-09-12 | criteria provided, single submitter | clinical testing | The SDHB c.178A>G (p.Thr60Ala) variant has been reported in the published literature in individuals with pheochromocytomas or paragangliomas (PMID: 34906457 (2022)), thyroid cancer (PMIDs: 29684080 (2018), 25694510 (2015)), breast cancer (PMID: 34326862 (2021)), and unspecified advanced cancer (28873162 (2017)). The frequency of this variant in the general population, 0.00011 (13/113648 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. |
St. |
RCV001294008 | SCV005689294 | uncertain significance | Paragangliomas 4 | 2024-07-08 | criteria provided, single submitter | clinical testing | The SDHB c.178A>G (p.Thr60Ala) missense change has a maximum frequency of 0.01% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/ ). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary paraganglioma-pheochromocytoma syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
Prevention |
RCV004732805 | SCV005350897 | uncertain significance | SDHB-related disorder | 2024-03-25 | no assertion criteria provided | clinical testing | The SDHB c.178A>G variant is predicted to result in the amino acid substitution p.Thr60Ala. This variant was reported in individuals with thyroid cancer, breast cancer, or pheochromocytomas/paragangliomas (Ni et al. 2015. PubMed ID: 25694510; eTable in Supplement 2, Mandelker et al. 2017. PubMed ID: 28873162; Penkert et al. 2018. PubMed ID: 30086788; Table S2, Garrett et al. 2022. PubMed ID: 34906457). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/239423/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |