ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9043A>G (p.Lys3015Glu) (rs587781497)

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Total submissions: 7
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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) RCV000989081 SCV001161626 benign Breast-ovarian cancer, familial 2 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 = 0.000831
Ambry Genetics RCV000129464 SCV000184234 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-23 criteria provided, single submitter clinical testing The p.K3015E variant (also known as c.9043A>G), located in coding exon 22 of the BRCA2 gene, results from an A to G substitution at nucleotide position 9043. The lysine at codon 3015 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified in 1/898 Greek families refered for BRCA1 and BRCA2 genetic testing (Apessos A et al. Cancer Genet, 2018 01;220:1-12). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000214548 SCV000279222 uncertain significance not provided 2015-12-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9043A>G at the cDNA level, p.Lys3015Glu (K3015E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). Using alternate nomenclature, this variant would be defined as BRCA2 9271A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys3015Glu 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 Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Lys3015Glu occurs at a position that is not conserved and is located in the DNA binding domain (Borg 2010). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Lys3015Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000533812 SCV000635713 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-16 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 3015 of the BRCA2 protein (p.Lys3015Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 141104). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 31131967). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Color Health, Inc RCV000129464 SCV000684019 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-19 criteria provided, single submitter clinical testing
Mendelics RCV000989081 SCV001139244 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001640120 SCV001852825 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation

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