ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1744A>G (p.Thr582Ala) (rs80358457)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000043870 SCV000071883 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-12-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 582 of the BRCA2 protein (p.Thr582Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (rs80358457, ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one of these individuals a pathogenic allele was also identified in BRCA1, which suggests that this c.1744A>G variant in BRCA2 was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 51181). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000130844 SCV000185742 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
GeneDx RCV000761856 SCV000210277 uncertain significance not provided 2016-11-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1744A>G at the cDNA level, p.Thr582Ala (T582A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). Using alternate nomenclature, this variant would be defined as BRCA2 1972A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Thr582Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Thr582Ala occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Thr582Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000112963 SCV000488224 uncertain significance Breast-ovarian cancer, familial 2 2016-01-27 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000761856 SCV000892062 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112963 SCV000145924 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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