ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221509 SCV000275166 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-06 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000416556 SCV000494429 uncertain significance not specified 2019-03-25 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.229A>G (p.Thr77Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246176 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant of interest has been reported in an affected individual (Lee_2008) and in several individuals undergoing for BRCA1/2 testing by clinical databases and labs, although with limited information (i.e. no co-occurrence and co-segregation data provided). Thus, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 whole gene deletion; BRCA1 c.5251C>T, p.Arg1751X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (3 VUS, 1 likely pathogenic). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508014 SCV000600506 likely pathogenic not provided 2016-11-29 criteria provided, single submitter clinical testing
Counsyl RCV000031361 SCV000785960 uncertain significance Breast-ovarian cancer, familial 2 2018-01-22 criteria provided, single submitter clinical testing
Mendelics RCV000031361 SCV001138948 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 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
Breast Cancer Information Core (BIC) (BRCA2) RCV000031361 SCV000146412 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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