ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3599_3600del (p.Asp1199_Cys1200insTer) (rs80359391)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162919 SCV000213406 pathogenic Hereditary cancer-predisposing syndrome 2018-04-02 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),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Breast Cancer Information Core (BIC) (BRCA2) RCV000113196 SCV000146265 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000162919 SCV000903412 pathogenic Hereditary cancer-predisposing syndrome 2017-03-29 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113196 SCV000326886 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000113196 SCV000488173 pathogenic Breast-ovarian cancer, familial 2 2016-01-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000195400 SCV000591871 pathogenic Hereditary breast and ovarian cancer syndrome 2013-11-15 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113196 SCV000300648 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 RCV000044230 SCV000210737 pathogenic not provided 2018-05-11 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.3599_3600delGT at the cDNA level and p.Cys1200Ter (C1200X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GACT[delGT]AACA. The deletion creates a nonsense variant, changing a Cysteine to a premature stop codon (TGT>TAA). 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 3827delGT or C1200fs*1 using alternate nomenclature, has been reported in association with hereditary breast and ovarian cancer and is thought to be a pathogenic founder variant in the Philippines and other Asian countries (De Leon Matsuda 2002, Liede 2002, Song 2014, Kang 2015, Nielsen 2016). We consider this variant to be pathogenic
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000113196 SCV000743287 pathogenic Breast-ovarian cancer, familial 2 2014-10-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000195400 SCV000916858 pathogenic Hereditary breast and ovarian cancer syndrome 2018-05-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3599_3600delGT (p.Cys1200X) 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 (e.g., p.Phe1216fsX2 and p.Leu1227fsX5). The variant allele was found at a frequency of 2e-05 in 249126 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (2e-05 vs 0.00075), allowing no conclusion about variant significance. The variant, c.3599_3600delGT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, indicating that the variant is very likely to be associated with disease (Song_2014, Hamann_2003. Kim_2012, Kang_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000195400 SCV000072243 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys1200*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80359391, ExAC 0.01%). This variant has been reported in individuals with breast cancer, ovarian cancer, and Fanconi anemia (PMID: 24504028, 16683254, 25863477, 15645491, 24728189). This variant is also known as 3827delGT in the literature. ClinVar contains an entry for this variant (Variation ID: 51493). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000044230 SCV000778665 pathogenic not provided 2017-11-30 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044230 SCV000600557 pathogenic not provided 2016-08-11 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000195400 SCV000587675 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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