ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6058G>A (p.Glu2020Lys) (rs80358842)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129466 SCV000184236 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113521 SCV000146756 uncertain significance Breast-ovarian cancer, familial 2 2000-06-12 no assertion criteria provided clinical testing
Color RCV000129466 SCV000903522 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing
Counsyl RCV000113521 SCV000487869 uncertain significance Breast-ovarian cancer, familial 2 2015-12-04 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000160106 SCV000592024 uncertain significance not specified 2015-03-27 criteria provided, single submitter clinical testing
GeneDx RCV000587558 SCV000210381 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6058G>A at the cDNA level, p.Glu2020Lys (E2020K) 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 6286G>A. This variant has been observed in at least two high-risk breast and/or ovarian cancer families as well as in one individual with glioblastoma multiforme (Hartmann 2001, Lu 2012, Lu 2015). BRCA2 Glu2020Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Glu2020Lys is located in the RAD51 binding domain (Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Glu2020Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587558 SCV000694931 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6058G>A (p.Glu2020Lys) variant involves the alteration of a conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 1/120632 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). Multiple publications have cited the variant in affected individuals, however, with limited information (ie, lack of co-occurrence and cosegregation data). One of the individuals reported by UMD also carried as a deleterious variant in BRCA1 c.4206_4207delTA (p.His1402GlnfsX11), supporting that this variant is not the primary cause of HBOC in the individual. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000471466 SCV000549600 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 2020 of the BRCA2 protein (p.Glu2020Lys). 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 (rs80358842, ExAC 0.002%). This variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 1169856, 22476429, 29470806), as well as in an individual affected with glioblastoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 126088). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Sharing Clinical Reports Project (SCRP) RCV000113521 SCV000189311 uncertain significance Breast-ovarian cancer, familial 2 2009-08-28 no assertion criteria provided clinical testing

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