ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7792GAA[1] (p.Glu2599del) (rs80359682)

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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 RCV000130941 SCV000185854 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-21 criteria provided, single submitter clinical testing The c.7795_7797delGAA variant (also known as p.E2599del) is located in coding exon 15 of the BRCA2 gene. This variant results from an in-frame GAA deletion at nucleotide positions 7795 to 7797. This results in the in-frame deletion of a glutamic acid at codon 2599. This alteration has been detected in several patients from breast and/or ovarian cancer cohorts (Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38; Rodríguez-Balada M et al. Cancer Genet, 2016 Nov;209:487-492; Labidi-Galy SI et al. Clin. Cancer Res., 2018 Jan;24:326-333; Caux-Moncoutier V et al. Hum. Mutat., 2011 Mar;32:325-34). This amino acid position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113819 SCV000327730 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000521346 SCV000617472 uncertain significance not provided 2017-05-16 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in BRCA2 is denoted c.7795_7797delGAA at the cDNA level and p.Glu2599del (E2599del) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 8023_8025delGAA. The normal sequence, with the bases that are deleted in brackets, is AGAA[delGAA]TTTTA. This deletion of a single Glutamic Acid residue occurs at a position that is conserved across species and is located in the DNA binding domain (Yang 2002). This variant has been reported in several individuals evaluated for Hereditary Breast and Ovarian Cancer (Coulet 2010, Caux-Moncoutier 2011, Lecarpentier 2012, Castera 2014, Radrigeuz-Balada 2016). Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA2 Glu2599del to be a variant of uncertain significance.
Mendelics RCV000113819 SCV001139192 likely pathogenic Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001037888 SCV001201323 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-06-23 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 16 of the BRCA2 mRNA (c.7795_7797delGAA). This leads to the deletion of 1 amino acid residue in the BRCA2 protein (p.Glu2599del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 20858050, 21120943, 24549055, 29240602). ClinVar contains an entry for this variant (Variation ID: 52409). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. 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 RCV000130941 SCV001340332 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-07 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001037888 SCV001478282 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-13 criteria provided, single submitter clinical testing Data included in classification: This variant is absent from population database gnomAD (PM2_mod) and has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 20858050, 21120943, 24549055 and 29240602) (PS4_mod). This variant is predicted to result in the deletion of 1 amino acid residue from the BRCA2 protein (p.Glu2599del) (PM4_sup). The deletion is within the BRCA2 binding domain (AA 2481-3156) a hotspot region as defined by the ENIGMA BRCA1/2 gene variant classification criteria (2017). Data not included in classification: Personal communication with French laboratories revealed the variant to be a well-known BRCA2 mutation, particularly in Northern France. Co-segregation analyses by French laboratories lead to a LR causality >310000 and to a posterior probability of 0.9999992447747283. This result has not been published (reported in ClinVar as pathogenic in 2005). Additional communication revealed the variant to have been observed in 87 French families but there is no information on population size. Rebbeck et al., 2018 (PMID:29446198) indicate that the variant is predicted to be associated with stable mutant proteins (BS3_sup).
Breast Cancer Information Core (BIC) (BRCA2) RCV000113819 SCV000147182 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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