ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5167A>G (p.Thr1723Ala) (rs80358742)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044582 SCV000072595 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1723 of the BRCA2 protein (p.Thr1723Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs80358742, ExAC 0.007%). This missense change has been observed in an individual affected with breast cancer (PMID: 21218378). ClinVar contains an entry for this variant (Variation ID: 51794). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000167513 SCV000218371 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000221189 SCV000279926 uncertain significance not specified 2017-04-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5167A>G at the cDNA level, p.Thr1723Ala (T1723A) 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 5395A>G. This variant was observed in an individual with two primary breast cancers, and also in her unaffected mother (Carney 2010). BRCA2 Thr1723Ala 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 Thr1723Ala occurs at a position that is not conserved and is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). 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 Thr1723Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000113392 SCV000785992 uncertain significance Breast-ovarian cancer, familial 2 2018-01-30 criteria provided, single submitter clinical testing
Color RCV000167513 SCV000906916 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985538 SCV001133819 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000221189 SCV001160151 uncertain significance not specified 2018-12-04 criteria provided, single submitter clinical testing The BRCA2 c.5167A>G; p.Thr1723Ala variant (rs80358742) is reported in the literature in an individual with breast cancer but also in her unaffected mother (Carney 2010). This variant is reported in ClinVar (Variation ID: 51794) and is found on five chromosomes in the Genome Aggregation Database. The threonine at codon 1723 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, given the lack of clinical and functional data, the significance of the p.Thr1723Ala variant is uncertain at this time. References: Carney ME et al. Detection of BRCA1 and BRCA2 mutations in a selected Hawaii population. Hawaii Med J. 2010 Nov;69(11):268-71.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113392 SCV000146555 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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