ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9253del (p.Thr3085fs) (rs80359752)

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Total submissions: 7
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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) RCV000257577 SCV000324753 pathogenic Breast-ovarian cancer, familial 2 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000045759 SCV000073772 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 24 of the BRCA2 mRNA (c.9253delA), causing a frameshift at codon 3085. This creates a premature translational stop signal (p.Thr3085Glnfs*19) 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 affected with breast cancer (PMID: 22382806, 25863477, 23593081). This variant is also known as 9481delA in the literature. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000236478 SCV000293489 pathogenic not provided 2017-07-11 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.9253delA at the cDNA level and p.Thr3085GlnfsX19 (T3085QfsX19) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAAAAAA[delA]CAGg, where the capital letters are exonic and the lower case are intronic. The deletion causes a frameshift which changes a Threonine to a Glutamine at codon 3085, and creates a premature stop codon at position 19 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.9253delA, also known as BRCA2 9481delA by alternate nomenclature, has been identified in multiple individuals with a personal or family history of breast cancer (Malone 2006, Kim 2012, Son 2012, Ou 2013, Kang 2015, Kim 2016, Park 2017). We consider this deletion to be a pathogenic variant.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000257577 SCV000328083 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000045759 SCV000605816 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-27 criteria provided, single submitter clinical testing The p.Thr3085fs variant in BRCA2 has been reported in at least 7 individuals wit h BRCA2-associated cancers (Kim 2012, Son 2012, Ou 2013, Kang 2015 ) and was abs ent from large population studies. This variant is predicted to cause a frameshi ft, which alters the protein?s amino acid sequence beginning at position 3085 an d leads to a premature termination codon 19 amino acids downstream. This alterat ion is then predicted to lead to a truncated or absent protein. Heterozygous los s of function of the BRCA2 gene is an established disease mechanism in hereditar y breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on October 18, 2016 by the ClinGen-approved ENIGMA expert panel (Clin Var SCV000324753.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner.
Ambry Genetics RCV000575819 SCV000668569 pathogenic Hereditary cancer-predisposing syndrome 2018-01-19 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)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236478 SCV000889180 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing

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