ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2884G>A (p.Glu962Lys) (rs80356955)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000111956 SCV001161497 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000971
Invitae RCV000195390 SCV000076013 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 962 of the BRCA1 protein (p.Glu962Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs80356955, ExAC 0.006%). This variant has been reported in an individual affected with breast cancer (PMID: 20104584). This variant is also known as 3003G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 54709). Experimental studies have shown that this missense change does not affect BRCA1 homologous 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 RCV000048000 SCV000210137 uncertain significance not provided 2018-11-06 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2884G>A at the cDNA level, p.Glu962Lys (E962K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant, also known as BRCA1 3003G>A using alternate nomenclature, has been observed in a woman with a history of unilateral breast cancer (Borg 2010). An in vitro-based homology-directed repair (HDR) assay showed this variant to exhibit HDR activity comparable to wildtype (Lu 2015). BRCA1 Glu962Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA and RAD51 binding domains (Chen 1998, Narod 2004). 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 BRCA1 Glu962Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000213861 SCV000272974 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048000 SCV000888875 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
Color RCV000213861 SCV000903258 benign Hereditary cancer-predisposing syndrome 2016-03-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779888 SCV000916775 uncertain significance not specified 2017-12-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2884G>A (p.Glu962Lys) variant involves the alteration of a non-conserved nucleotide, that results in the substitution of a glutamine amino acid for lysine in the DNA binding domain of the BRCA1 protein (Lu 2015). Since a lysine amino acid residue is found in multiple mammalian species at this position, this suggests that the variant of interest might not adversely affect protein function. 3/5 in silico tools predict a benign outcome for this variant. Moreover, in a functional study the variant protein was found to have a similar homology-directed repair (HDR) activity to the wild type protein (Lu 2015). This variant was found in 4/277044 control chromosomes at a frequency of 0.0000144, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). Though the variant has been reported in HBOC patients (Judkins 2005, Borg 2010), no convincing evidence was provided for causality. This variant has been reported in five patients in the UMD database, however a pathogenic BRCA2 variant (c.145G>T (p.Glu49X)) was also present in one of the patients, suggesting that the variant of interest was not the primary cause of disease in this patient. Though multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, considering all the available evidence, this variant is classified as VUS possibly benign.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111956 SCV000144570 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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