ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9076C>T (p.Gln3026Ter) (rs80359159)

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Total submissions: 17
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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) RCV000031790 SCV000301347 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000045706 SCV000073719 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln3026*) 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 and/or ovarian cancer (PMID: 11595708, 22632462, 26187060, 19016756, 28205045, 25863477), male breast cancer (PMID: 28008555), and pancreatic ductal adenocarcioma (PMID: 27732944). ClinVar contains an entry for this variant (Variation ID: 38207). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131038 SCV000185968 pathogenic Hereditary cancer-predisposing syndrome 2018-01-03 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),Deficient protein function in appropriate functional assay(s)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031790 SCV000328043 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000413921 SCV000490440 pathogenic not provided 2017-12-28 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9076C>T at the cDNA level and p.Gln3026Ter (Q3026X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Additionally, Acedo et al. (2012) showed via minigene assay that BRCA2 Gln3026Ter produces an aberrant splicing pattern due to the creation of an exon splice silencer, with the majority of the affected transcript predicted to result in premature truncation and undergo nonsense mediated mRNA decay (87.5%), and a minority resulting in exon 23 skipping (9.3%), exon 23 and 24 skipping (1.9%), and a 51 base deletion in exon 23 (1.3%). This variant, previously reported as BRCA2 9304C>T using alternate nomenclature, has been observed in multiple individuals with breast, ovarian, and/or pancreatic cancer (Ikeda 2001, Sekine 2001, Sugano 2008, Kim 2012, Kang 2015, Takai 2016, Pritzlaff 2017) and is considered pathogenic.
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000045706 SCV000586988 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045706 SCV000592252 pathogenic Hereditary breast and ovarian cancer syndrome 2013-05-13 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031790 SCV000743358 pathogenic Breast-ovarian cancer, familial 2 2014-10-08 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000031790 SCV000746275 pathogenic Breast-ovarian cancer, familial 2 2017-12-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000413921 SCV000883483 pathogenic not provided 2017-05-31 criteria provided, single submitter clinical testing The BRCA2 c.9076C>T, p.Gln3026Ter variant (rs80359159) has been reported in a family with breast and ovarian cancer (Sekine 2001). Minigene analysis indicates that the variant generates a transcript that leads to a premature termination codon through a frameshift or nonsense codon, or a transcript lacking 2 exons and approximately 101 amino acids (Acedo 2012). The variant is classified as pathogenic in ClinVar (Variation ID: 38207), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Acedo A et al. Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes. Breast Cancer Res. 2012; 14(3):R87. Sekine M et al. Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population. Clin Cancer Res. 2001; 7(10):3144-50.
Color RCV000131038 SCV000911637 pathogenic Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045706 SCV000916964 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9076C>T (p.Gln3026X) 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. c.9093_9094delinsG/p.Thr3033fsX29, c.9097dupA/p.Thr3033fsX11). The variant was absent in 246292 control chromosomes (gnomAD). c.9076C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Malone_2006, Kang_2015, Palmero_2018). These data indicate that the variant is very likely to be associated with disease. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.6237_6238delGT, p.Leu2080ArgfsX4) possibly in a patient with Fanconi Anemia (BRCA Share database). One study showed this variant did not significantly affect splicing (Acedo_2012). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000045706 SCV000966961 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-18 criteria provided, single submitter clinical testing The p.Gln3026X variant in BRCA2 has been reported in >10 individuals with BRCA2- associated cancers (Ikeda 2001, Sekine 2001, Sugano 2008, Kang 2015, Arai 2018). It was also absent from large population studies. This nonsense variant leads t o a premature termination codon at position 3026, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene i s an established disease mechanism in hereditary breast and ovarian cancer (HBOC ). In addition, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 38207). In summary, the p.Gln 3026X variant meets criteria to be classified as pathogenic for HBOC in an autos omal dominant manner. ACMG/AMP criteria applied: PVS1, PS4_Moderate, PM2.
Sharing Clinical Reports Project (SCRP) RCV000031790 SCV000054398 pathogenic Breast-ovarian cancer, familial 2 2013-01-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031790 SCV000147529 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031790 SCV000733329 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735618 SCV000863756 pathogenic Breast and/or ovarian cancer 2014-07-30 no assertion criteria provided clinical testing

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