ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7762_7764delinsTT (p.Ile2588fs) (rs483353072)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222283 SCV000277871 pathogenic Hereditary cancer-predisposing syndrome 2015-08-12 criteria provided, single submitter clinical testing
Color RCV000222283 SCV000689066 pathogenic Hereditary cancer-predisposing syndrome 2016-10-19 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000225480 SCV000327726 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) RCV000225480 SCV000282449 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000254816 SCV000322114 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted BRCA2 c.7762_7764delATAinsTT at the cDNA level and p.Ile2588PhefsX60 (I2588FfsX60) at the protein level. The normal sequence, with the bases that are deleted and inserted in brackets, is GCTC[delATA][insTT]CCCT. The variant causes a frameshift, which changes an Isoleucine to a Phenylalanine at codon 2588, and creates a premature stop codon at position 60 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.7762_7764delATAinsTT, previously reported as 7990delATAinsTT and 7990delATAins2, has been reported in at least two individuals with a personal and/or family history consistent with hereditary breast and ovarian cancer (Evans 2003, Borg 2010). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000476038 SCV000918917 pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-26 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7762_7764delinsTT (p.Ile2588PhefsX60) 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. p.Trp2626X, p.Met2634fsX14, and p.Arg2645fsX3). The variant was absent in 246218 control chromosomes (gnomAD). The variant, c.7762_7764delinsTT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Evans_2003, Lai_2015, Watson_2014, Borg_2010, Spearman_2008, Palma_2008). 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. Eight 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 RCV000476038 SCV000549642 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides and inserts 2 nucleotides in exon 16 of the BRCA2 mRNA (c.7762_7764delinsTT), causing a frameshift at codon 2588. This creates a premature translational stop signal (p.Ile2588Phefs*60) and is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with breast and/or ovarian cancer (PMID: 15131399, 12960223, 20104584). This variant is also known in the literature as 7990delATAinsTT and 7990del3ins2. ClinVar contains an entry for this variant (Variation ID: 233493). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000476038 SCV000605779 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-02 criteria provided, single submitter clinical testing The p.Ile2588fs (c.7762_7764delinsTT) variant in BRCA2 has been reported in at l east 8 individuals with BRCA2-associated cancers (Evans 2003, Lai 2015, Breast C ancer Information Core database, www.research.nhgri.nih.gov/bic/). While this va riant 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 fr ameshift, which alters the protein?s amino acid sequence beginning at position 2 588 and leads to a premature termination codon 60 amino acids downstream. This a lteration is then predicted to lead to a truncated or absent protein. Heterozygo us loss of function of the BRCA2 gene is an established disease mechanism in her editary breast and ovarian cancer (HBOC). Additionally, the p.Ile2588fs variant has been classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIG MA Expert Panel (ClinVar SCV000282449.1). In summary, this variant meets our cri teria to be classified as pathogenic for HBOC in an autosomal dominant manner ba sed upon the predicted impact to the protein and presence in multiple affected i ndividuals.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000225480 SCV000296731 pathogenic Breast-ovarian cancer, familial 2 2015-02-18 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000476038 SCV000587908 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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