ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.446A>C (p.Glu149Ala) (rs397507233)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240737 SCV000265873 uncertain significance Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Ambry Genetics RCV000219296 SCV000274232 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-19 criteria provided, single submitter clinical testing
Invitae RCV000458634 SCV000549301 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 149 of the BRCA1 protein (p.Glu149Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs397507233, ExAC 0.07%). This variant has been reported in individuals affected with breast cancer (PMID: 22116506, 27257965) and stomach cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 37594). Experimental studies have shown that this missense change does not impact BRCA1 homology-directed repair activity (PMID: 26689913). 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.
GeneDx RCV000479398 SCV000570422 uncertain significance not provided 2018-09-25 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.446A>C at the cDNA level, p.Glu149Ala (E149A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAA>GCA). Using alternate nomenclature, this variant would be defined as BRCA1 565A>C. This variant was observed in several individuals with breast cancer and in one individual with gastric cancer (Zhang 2012, Lu 2015, Zhong 2016, Wei 2018). Functional analysis of this variant showed no significant difference as compared to wild type in a homologous directed repair assay (Lu 2015). BRCA1 Glu149Ala was observed at an allele frequency of 0.06% (12/18870) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located within a region that binds BRD7 (Harte 2010). Protein-based in silico analysis, which includes protein predictors and evolutionary conservation, predicts that this variant is probably damaging to protein structure and function, and splicing models are uninformative in their assessment as to whether or not the variant is damaging. Based on currently available evidence, it is unclear whether BRCA1 Glu149Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000764128 SCV000895101 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; FANCONI ANEMIA, COMPLEMENTATION GROUP S 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000219296 SCV000910906 likely benign Hereditary cancer-predisposing syndrome 2016-04-19 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031175 SCV000053775 uncertain significance Breast-ovarian cancer, familial 1 2008-09-04 no assertion criteria provided clinical testing

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