ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5782G>A (p.Glu1928Lys) (rs56253082)

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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 RCV000164827 SCV000215510 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting pathogenic classification,Insufficient evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077360 SCV000146697 uncertain significance Breast-ovarian cancer, familial 2 2000-06-12 no assertion criteria provided clinical testing
Color RCV000164827 SCV000688949 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-14 criteria provided, single submitter clinical testing
GeneDx RCV000586545 SCV000329137 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5782G>A at the cDNA level, p.Glu1928Lys (E1928K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Using alternate nomenclature, this variant would be defined as BRCA2 6010G>A. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Glu1928Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51 binding domain (Roy 2012). 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 Glu1928Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586545 SCV000694902 uncertain significance not provided 2017-08-03 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5782G>A (p.Glu1928Lys) variant involves the alteration of a non-conserved nucleotide. Although glutamic acid and lysine differ in charge, 4/5 in silico tools predict a benign outcome for this variant. This variant is absent in 121046 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant was reported in a database (BIC) in two individuals who carried another pathogenic BRCA1 variant, c.66_67delAG (p.Glu23fsX17) and a likely pathogenic BRCA1 variant, c.5359T>A_c.5363G>A (p.Cys1787Ser_p.Gly1788Asp), respectively. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000044753 SCV000072766 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1928 of the BRCA2 protein (p.Glu1928Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one of these individuals a pathogenic allele was also identified in BRCA1, which suggests that this c.5782G>A variant in BRCA2 was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 51936). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077360 SCV000296669 uncertain significance Breast-ovarian cancer, familial 2 2016-05-05 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077360 SCV000109157 uncertain significance Breast-ovarian cancer, familial 2 2012-07-02 no assertion criteria provided clinical testing

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