ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2024C>G (p.Thr675Arg) (rs80358484)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222018 SCV000276242 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113006 SCV000145992 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Color RCV000222018 SCV000906887 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Counsyl RCV000113006 SCV000785208 uncertain significance Breast-ovarian cancer, familial 2 2017-06-02 criteria provided, single submitter clinical testing
GeneDx RCV000481560 SCV000569252 uncertain significance not provided 2016-12-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2024C>G at the cDNA level, p.Thr675Arg (T675R) at the protein level, and results in the change of a Threonine to an Arginine (ACA>AGA). Using alternate nomenclature, this variant would be defined as BRCA2 2252C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Thr675Arg 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 Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Thr675Arg occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Thr675Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168556 SCV000071948 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-05-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 675 of the BRCA2 protein (p.Thr675Arg). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 51236). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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