ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9364G>A (p.Ala3122Thr) (rs587782313)

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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 RCV000131208 SCV000186158 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence,Other data supporting benign classification
Invitae RCV000485860 SCV000218682 likely benign not provided 2018-11-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000238950 SCV000296561 uncertain significance Breast-ovarian cancer, familial 2 2016-03-12 criteria provided, single submitter clinical testing
GeneDx RCV000485860 SCV000567129 uncertain significance not provided 2016-08-25 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9364G>A at the cDNA level, p.Ala3122Thr (A3122T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). Using alternate nomenclature, this variant has been previously published as BRCA2 9592G>A. BRCA2 Ala3122Thr was observed in two unrelated Moroccan patients with familial breast cancer and was reported to co-occur with the same pathogenic variant in BRCA2 in both patients (Tazzite 2012). BRCA2 Ala3122Thr 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 Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala3122Thr occurs at a position that is conserved in mammals and is located within the DNA binding domain (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, while classification by a multifactorial likelihood model suggests that this variant is likely not pathogenic (Whiley 2014). Based on currently available evidence, it is unclear whether BRCA2 Ala3122Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000238950 SCV000786523 likely benign Breast-ovarian cancer, familial 2 2018-05-18 criteria provided, single submitter clinical testing
Color RCV000131208 SCV000911226 likely benign Hereditary cancer-predisposing syndrome 2017-01-16 criteria provided, single submitter clinical testing

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