ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.229A>G (p.Thr77Ala) (rs80358500)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221509 SCV000275166 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000031361 SCV000146412 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Counsyl RCV000031361 SCV000785960 uncertain significance Breast-ovarian cancer, familial 2 2018-01-22 criteria provided, single submitter clinical testing
GeneDx RCV000508014 SCV000566296 uncertain significance not provided 2018-02-08 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.229A>G at the cDNA level, p.Thr77Ala (T77A) 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 457A>G. This variant has been observed in at least one individual with early-onset breast cancer (Lee 2008). While BRCA2 Thr77Ala has been demonstrated to disrupt the interaction of BRCA2 with PLK1, it is unclear whether this lack of binding influences cancer development (Yata 2014, Takaoka 2014). BRCA2 Thr77Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Thr77Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000416556 SCV000494429 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-02-29 criteria provided, single submitter clinical testing Variant Summary: The variant of interest causes a misense change involving a conserved nucleotide with 5/5 in silico programs predicting a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121186 (1/60593), which does not exceed the predicted maximum expected allele frequency for a pathogenic BRCA2 variant of 1/1333. The variant of interest has been reported in affected individual(s) via a publication, although with limited information (ie lack of co-occurrence and co-segregation data). A functional study implicates the variant of interest to affect phosphorylation, however, the role of this has not been well-established for carcinogenesis. In addition, multiple reputable databases/clinical laboratories cite the variant with a classification of "uncertain significance." BIC reports the variant to co-occur with a pathogenic BRCA1 variant, suggesting a benign role of the variant. Taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508014 SCV000600506 likely pathogenic not provided 2016-11-29 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031361 SCV000053966 uncertain significance Breast-ovarian cancer, familial 2 2012-04-12 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.