Submissions for variant NM_000059.4(BRCA2):c.7762del (p.Ile2588fs)

dbSNP: rs80359679

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113814	SCV000301202	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000509870	SCV000608142	pathogenic	Hereditary cancer-predisposing syndrome	2018-04-18	criteria provided, single submitter	clinical testing	The c.7762delA pathogenic mutation, located in coding exon 15 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 7762, causing a translational frameshift with a predicted alternate stop codon (p.I2588Yfs*60). This pathogenic mutation has been reported in an early-onset breast cancer family and in a series of >900 epithelial ovarian cancer patients (Frank TS et al. J. Clin. Oncol. 1998 Jul;16:2417-25; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026). In one case control study, this alteration was detected in 2/2222 individuals with high-grade serous epithelial ovarian cancer and 0/1528 matched controls. (Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9). Of note, this mutation is also designated as 7990delA and I2588fs in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
CSER _CC_NCGL, University of Washington	RCV000045307	SCV000700127	pathogenic	Hereditary breast ovarian cancer syndrome	2016-10-01	criteria provided, single submitter	research	Found in a male patient having exome sequencing for an unrelated indication with a family history of breast and pancreatic cancer. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Genetics and Molecular Pathology, SA Pathology	RCV000113814	SCV002556628	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-05-11	criteria provided, single submitter	clinical testing	The BRCA2 c.7762del variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) This BRCA2 c.7762del variant is located in exon 16/27 and is predicted to cause a shift in the reading frame at codon 2588. BRCA2:c. 7762del (also described as BRCA1 4184del4 using legacy nomenclature) has been reported in multiple unrelated individuals and families with breast, ovarian and colon cancer (Cunningham et al., 2015 PMID: 24504028; Rosenthal et al, 2018 PMID: 30267214; Copson et al, 2018 PMID: 29337092). (Ps4_moderate) The variant has been reported in dbSNP (rs80359679) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 52405). It has not been reported in HGMD. literature: Frank (1998) J Clin Oncol, Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. PubMed: 9667259
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045307	SCV004021071	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7762delA (p.Ile2588TyrfsX60) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251436 control chromosomes (gnomAD). c.7762delA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Lilyquist_2017). The following publication has been ascertained in the context of this evaluation (PMID: 28888541). Four submitters, including an expert panel, have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000045307	SCV004847973	pathogenic	Hereditary breast ovarian cancer syndrome	2015-12-04	criteria provided, single submitter	clinical testing	The p.Ile2588fs variant in BRCA2 has been reported in 3 individuals with breast and/or ovarian cancers (Frank 1998, Cunningham 2014; Breast Cancer Information Core database, www.research.nhgri.nih.gov/bic/). While this variant was absent from large population studies, the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2588 and leads to a premature termination codon 60 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) for hereditary breast and ovarian cancer in an autosomal dominant manner based upon the predicted impact to the protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045307	SCV000073320	pathogenic	Hereditary breast ovarian cancer syndrome	2014-06-11	no assertion criteria provided	clinical testing	The interpretation for this sequence variant was made by Invitae based on the ACMG guidelines. A more detailed explanation of the interpretation for this specific variant is forthcoming. This ClinVar entry will be updated at that time.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113814	SCV000147176	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045307	SCV000587907	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research