ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9433_9434GT[1] (p.Ser3147fs) (rs80359763)

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Total submissions: 15
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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) RCV000031823 SCV000301391 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 RCV000235145 SCV000108648 pathogenic not provided 2018-04-18 criteria provided, single submitter clinical testing This deletion of two nucleotides in BRCA2 is denoted c.9435_9436delGT at the cDNA level and p.Ser3147CysfsX2 (S3147CfsX2) at the protein level. This deletion is also known as BRCA2 9433delGT, 9663_9664delGT and 9663delGT using alternate nomenclature. The normal sequence, with the bases that are deleted in brackets, is CTGT[delGT]TTTC. The deletion causes a frameshift, which changes a Serine to a Cysteine at codon 3147, and creates a premature stop codon at position 2 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.9435_9436delGT has been observed in familial breast and ovarian cancer cases (Phelan 1996, Kim 2012, Cunningham 2014, Hong 2016) and is considered pathogenic.
Ambry Genetics RCV000131046 SCV000185976 pathogenic Hereditary cancer-predisposing syndrome 2017-04-07 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)
Invitae RCV000205868 SCV000259805 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser3147Cysfs*2) in the BRCA2 gene. It 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 individuals affected with breast cancer (PMID: 8673090, 22798144, 18489799, 21913181), ovarian cancer (PMID: 24504028), and an individual with male breast cancer and melanoma (PMID: 28008555). This variant is also known as 9433delGT, 9663delGT and 3144_3145del in the literature. ClinVar contains an entry for this variant (Variation ID: 38240). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine,University of Washington RCV000210147 SCV000266053 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031823 SCV000328134 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031823 SCV000487799 pathogenic Breast-ovarian cancer, familial 2 2015-11-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000205868 SCV000592288 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235145 SCV000600861 pathogenic not provided 2017-04-28 criteria provided, single submitter clinical testing
Color RCV000131046 SCV000689196 pathogenic Hereditary cancer-predisposing syndrome 2016-04-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778392 SCV000914621 pathogenic BRCA2-Related Disorders 2018-08-15 criteria provided, single submitter clinical testing The BRCA2 c.9435_9436delGT (p.Ser3147CysfsTer2) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Ser3147CysfsTer2 variant has been found in a heterozygous state in at least four patients with hereditary breast and ovarian cancer (HBOC), including in one male with breast cancer, in two individuals with breast and/or ovarian cancer and in one individual with ovarian cancer (Kim et al. 2012; Litton et al. 2012; Cunningham et al. 2014; Pritzlaff et al. 2017). The variant was also identified in a heterozygous state in three at-risk individuals with a family history of early-onset breast and ovarian cancer (Lubinski et al. 2004; Machackova et al. 2008; Bellacosa et al. 2010). This variant has not been described in the literature in patients with Fanconi anemia (FA), however, it is generally accepted that heterozygous variants pathogenic for HBOC confer carrier status for FA. Control data are unavailable for this variant which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence and the potential impact of frameshift variants, the p.Ser3147CysfsTer2 variant is classified as pathogenic for BRCA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000205868 SCV000918909 pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-24 criteria provided, single submitter clinical testing Variant summary: The c.9435_9436delGT (p.Ser3147CysfsX2) variant in BRCA2 gene is a frameshift change that results in the loss of the ~271 amino acids of brca2 protein (~10%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. In addition, truncations downstream of this position have been classified as pathogenic/likely pathogenic by our laboratory (e.g. p.Arg3268fsX9, p.Lys3263fsX12, p.Tyr3308X, etc). The variant is present at a low frequency in the large control population datasets of gnomAD (0.000004; 1/246128 chrs tested). The c.9435_9436delGT has been reported in multiple affected individuals with personal and family history of BrC via published report. Lastly, it is cited as Pathogenic by reputable databases/clinical laboratories. Taking together, the variant was classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031823 SCV000054431 pathogenic Breast-ovarian cancer, familial 2 2012-10-10 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031823 SCV000147636 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 RCV000205868 SCV000588006 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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