ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9026_9030del (p.Tyr3009fs) (rs80359741)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214145 SCV000276449 pathogenic Hereditary cancer-predisposing syndrome 2018-02-13 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) RCV000031787 SCV000147516 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000214145 SCV000684017 pathogenic Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031787 SCV000328030 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031787 SCV000677704 pathogenic Breast-ovarian cancer, familial 2 2017-02-08 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031787 SCV000301339 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 RCV000414452 SCV000490438 pathogenic not provided 2018-02-22 criteria provided, single submitter clinical testing This deletion of 5 nucleotides in BRCA2 is denoted c.9026_9030delATCAT at the cDNA level and p.Tyr3009SerfsX7 (Y3009SfsX7) at the protein level. The normal sequence, with the bases that are deleted in braces, is ATTT[ATCAT]CTTG. The deletion causes a frameshift which changes a Tyrosine to a Serine at codon 3009, and creates a premature stop codon at position 7 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.9026_9030delATCAT, previously reported as c.9254_9258delATCAT and 9254del5, has been identified in several hereditary breast /ovarian cancer families and has been reported as a founder variant in Northern Spanish populations (Tavtigian 1996, Blay 2013, Caputo 2011, de Juan Jimenez 2013). We consider this variant to be pathogenic.
Genetic Services Laboratory, University of Chicago RCV000031787 SCV000593757 pathogenic Breast-ovarian cancer, familial 2 2017-05-30 criteria provided, single submitter clinical testing
Genologica Medica RCV000031787 SCV000577974 pathogenic Breast-ovarian cancer, familial 2 2017-01-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045692 SCV000916948 pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-12 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9026_9030delATCAT (p.Tyr3009SerfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.9076C>T, p.Gln3026X; c.9093_9094delinsG, p.Thr3033fsX29; c.9097dupA, p.Thr3033fsX11). The variant allele was found at a frequency of 4.1e-06 in 245684 control chromosomes (gnomAD and literature). c.9026_9030delATCAT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Serova-Sinilnikova_1997, Neuhausen_1998, Campos_2003, Beristain_2007, Labidi-Galy_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000045692 SCV000073705 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-25 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 23 of the BRCA2 mRNA (c.9026_9030delATCAT), causing a frameshift at codon 3009. This creates a premature translational stop signal (p.Tyr3009Serfs*7) 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 the literature in individuals and families affected with breast and/or ovarian cancer (PMID: 8589730, 12655574, 22632462, 23479189, 26026974). This variant is a common cause of breast/ovarian cancer among Spanish populations (PMID: 12655574, 23479189, 26026974, 25586199). It is also known as 9254del5 in the literature. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000414452 SCV000296639 pathogenic not provided 2015-11-17 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031787 SCV000054395 pathogenic Breast-ovarian cancer, familial 2 2011-06-30 no assertion criteria provided clinical testing

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