ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1763_1766del (p.Asn588fs) (rs80359303)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000254640 SCV000885092 pathogenic not provided 2017-11-20 criteria provided, single submitter clinical testing The BRCA2 c.1763_1766delATAA; p.Asn588fs (traditionally known as 1991_1994del4) is published in the medical literature in individuals and families with breast cancer (Kanaan 2003, Torres 2017). The variant is listed in the ClinVar database (Variation ID: 51187), in the dbSNP variant database (rs80359303), but not in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The variant deletes four nucleotides, results in a premature termination codon, and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as pathogenic. References: Kanaan Y et al. Inherited BRCA2 mutations in African Americans with breast and/or ovarian cancer: a study of familial and early onset cases. Hum Genet. 2003 Oct;113(5):452-60. Torres D et al. Prevalence and Penetrance of BRCA1 and BRCA2 Germline Mutations in Colombian Breast Cancer Patients. Sci Rep. 2017 Jul 5;7(1):4713.
Ambry Genetics RCV000131054 SCV000185984 pathogenic Hereditary cancer-predisposing syndrome 2017-01-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Breast Cancer Information Core (BIC) (BRCA2) RCV000077264 SCV000145927 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131054 SCV000683444 pathogenic Hereditary cancer-predisposing syndrome 2016-05-22 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077264 SCV000326605 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077264 SCV000300460 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000254640 SCV000108600 pathogenic not provided 2017-12-21 criteria provided, single submitter clinical testing This deletion of four nucleotides in BRCA2 is denoted c.1763_1766delATAA at the cDNA level and p.Asn588SerfsX25 (N588SfsX25) at the protein level. Using alternate nomenclature, this variant has been published as BRCA2 1991del4. The normal sequence, with the bases that are deleted in brackets, is ACAA[delATAA]GTTT. The deletion causes a frameshift, which changes an Asparagine to a Serine at codon 588, and creates a premature stop codon at position 25 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.1763_1766delATAA has been reported in multiple families with Hereditary Breast and Ovarian Cancer syndrome (Kanaan 2003, Laitman 2011, Torres 2017, Yang 2017). We consider this variant to be pathogenic.
GeneKor MSA RCV000074515 SCV000296843 pathogenic Familial cancer of breast 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000043877 SCV000918814 pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-13 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1763_1766delATAA (p. Asn588SerfsX25) variant results in a 4 nucleotides deletion from exon 10 of the BRCA2 mRNA, causing a frameshift that creates a premature stop codon. This is predicted to cause a truncated or absent (due to nonsense mediated decay) BRCA2 protein, which is a commonly known mechanism for disease. This variant was not found in a large and broad control population (0/246896 control chromosomes in gnomAD and publications). This variant has been reported in numerous HBOC patients in the literature (Laitman 2011, Dobricic 2013, Tea 2014, Torres 2017, Yang 2017). In addition, multiple clinical laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Invitae RCV000043877 SCV000071890 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-09 criteria provided, single submitter clinical testing This sequence change deletes 4 nucleotides from exon 10 of the BRCA2 mRNA (c.1763_1766delATAA), causing a frameshift at codon 588. This creates a premature translational stop signal (p.Asn588Serfs*25) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic. This particular variant has been reported in patients and families affected with breast cancer and ovarian cancer (PMID: 12942367, 25415331, 20960228). This variant is also known as 1991delATAA, and 1991del4 in the literature. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000043877 SCV000605801 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-04 criteria provided, single submitter clinical testing The p.Asn588fs variant in BRCA2 has been reported in 7 individuals with BRCA2-as sociated cancers (Laitman 2011, Kanaan 2003, Dobricic 2013, Breast Cancer Inform ation Core (BIC) database) and was absent from large population studies. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 588 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncate d or absent protein. Heterozygous loss of function of the BRCA2 gene is an estab lished disease mechanism in individuals with hereditary breast and ovarian cance r (HBOC). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300460.2). In s ummary, the p.Asn588fs variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon absence from controls and t he predicted impact to the protein.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254640 SCV000887758 pathogenic not provided 2018-03-14 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000043877 SCV000587608 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077264 SCV000109061 pathogenic Breast-ovarian cancer, familial 2 2011-06-23 no assertion criteria provided clinical testing

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