ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.771_775del (p.Asn257fs) (rs80359671)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000009913 SCV000300360 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000195405 SCV000073307 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn257Lysfs*17) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80359671, ExAC 0.02%). This variant is a common cause of breast and ovarian cancer in the Icelandic population (PMID: 9150155, 8673089), and has been reported in individuals of other ethnicities (PMID: 8589730, 25863477, 24549055). This variant is also known as 999del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 9326). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131848 SCV000186903 pathogenic Hereditary cancer-predisposing syndrome 2016-09-29 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)
GeneDx RCV000212208 SCV000210707 pathogenic not provided 2018-01-31 criteria provided, single submitter clinical testing This deletion of five nucleotides in BRCA2 is denoted c.771_775delTCAAA at the cDNA level and p.Asn257LysfsX17 (N257KfsX17) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAAA[delTCAAA]GAGA. The deletion causes a frameshift, which changes an Asparagine to a Lysine at codon 257, and creates a premature stop codon at position 17 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. This variant, previously reported as BRCA2 999del5, is a founder pathogenic variant in Iceland, accounting for 7-8% of all breast and ovarian cancer in the country, and has been shown in expression studies to be extremely unstable and to impact cytokinesis (Johannesdottir 1996, Thorlacius 1997, Mikaelsdottir 2004, Jonsdottir 2009). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000009913 SCV000296746 pathogenic Breast-ovarian cancer, familial 2 2015-02-02 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000009913 SCV000327719 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000009913 SCV000488124 pathogenic Breast-ovarian cancer, familial 2 2016-01-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000195405 SCV000591710 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000009913 SCV000605700 pathogenic Breast-ovarian cancer, familial 2 2016-12-19 criteria provided, single submitter clinical testing
Color RCV000131848 SCV000683900 pathogenic Hereditary cancer-predisposing syndrome 2017-01-02 criteria provided, single submitter clinical testing
GeneKor MSA RCV000056288 SCV000693552 pathogenic Familial cancer of breast 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000195405 SCV000695095 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-04 criteria provided, single submitter clinical testing Variant summary: The c.771_775delTCAAA variant is predicted to cause a frameshift, which alters the proteins amino acid sequence beginning at position 257 and leads to a premature termination codon 16 amino acids downstream. It is predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.Glu260fs). Mutation taster predicts damaging outcome for this variant. This variant is found in 2/113322 control chromosomes at a frequency of 0.0000176, which does not exceed maximal expected frequency of a pathogenic allele (0.0007503). This variant has been reported in numerous BrC/OvC/PrC patients and is considered to be a founder mutation that accounts for 78% of female breast cancers and for 40% of male breast cancers in Iceland. In addition, multiple clinical laboratories/reputable databases (UMD, BIC, ARUP) classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000009913 SCV000744392 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212208 SCV000887922 pathogenic not provided 2015-02-02 criteria provided, single submitter clinical testing
OMIM RCV000009913 SCV000030134 pathogenic Breast-ovarian cancer, familial 2 2000-05-01 no assertion criteria provided literature only
GeneReviews RCV000056288 SCV000086655 pathologic Familial cancer of breast 2013-09-26 no assertion criteria provided curation Converted during submission to Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000009913 SCV000109205 pathogenic Breast-ovarian cancer, familial 2 2012-10-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000009913 SCV000147710 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000195405 SCV000587570 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000009913 SCV000733217 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing

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