ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5645C>A (p.Ser1882Ter) (rs80358785)

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Total submissions: 22
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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) RCV000031565 SCV000282410 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000167830 SCV000072718 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser1882*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80358785, ExAC 0.01%). This variant has been reported in several individuals and families affected with breast, ovarian and prostate cancer (PMID: 22144684, 22535016, 22666503, 21952622, 15024741). This variant is also known as 5873C>A in the literature. ClinVar contains an entry for this variant (Variation ID: 37984). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this sequence change has been classified as Pathogenic.
Ambry Genetics RCV000131114 SCV000186044 pathogenic Hereditary cancer-predisposing syndrome 2018-02-23 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)
GeneDx RCV000044705 SCV000210359 pathogenic not provided 2018-05-15 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.5645C>A at the cDNA level and p.Ser1882Ter (S1882X) at the protein level. The substitution creates a nonsense variant, changing a Serine to a premature stop codon (TCA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as BRCA2 5873C>A using alternate nomenclature, has been reported in multiple individuals and families with breast and/or ovarian cancer as well as in two siblings with with Fanconi Anemia and is considered pathogenic (De Benedetti 1998, Reid 2005, Weren 2016, Zhong 2016, Takahashi 2017).
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240722 SCV000265907 pathogenic Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031565 SCV000327251 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044705 SCV000600653 pathogenic not provided 2017-04-03 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000031565 SCV000605680 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Color RCV000131114 SCV000683721 pathogenic Hereditary cancer-predisposing syndrome 2017-02-21 criteria provided, single submitter clinical testing
GeneKor MSA RCV000585709 SCV000693572 pathogenic Familial cancer of breast 2017-11-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000167830 SCV000694888 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-31 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5645C>A (p.Ser1882X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/120628 (1/40160, 0.0000249), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333 (0.0007503). In addition, it needs to be noted that these three occurrences need to be cautiously considered due to the fact that the ExAC cohort contains individuals that could harbor a BRCA2 phenotype. However, multiple affected individuals have been reported via publications, along with numerous reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031565 SCV000743309 pathogenic Breast-ovarian cancer, familial 2 2014-10-08 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031565 SCV000744472 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735569 SCV000902206 pathogenic Breast and/or ovarian cancer 2017-03-17 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000167830 SCV000967739 pathogenic Hereditary breast and ovarian cancer syndrome 2018-01-17 criteria provided, single submitter clinical testing The p.Ser1882X variant in BRCA2 has been reported in >60 individuals with BRCA2- associated cancers and segregated with disease in 2 affected relatives from 2 fa milies (Caputo 2012, De Silva 2017, Heidemann2012, Rebbeck 2016, Reid 2005). Thi s variant has also been identified in 1/17202 East Asian and 2/110946 European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs80358785). This nonsense variant leads to a premature terminati on codon at position 1882, which is predicted to lead to a truncated or absent p rotein. Heterozygous loss of function of the BRCA2 gene is an established diseas e mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this va riant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENI GMA expert panel (ClinVar SCV000282410.1). In summary, this variant meets criter ia to be classified as pathogenic for HBOC in an autosomal dominant manner based upon predicted impact to the protein, absence in the general population and pre sence in multiple affected individuals. ACMG/AMP Criteria applied: PVS1; PS4; PM 2 (Richards 2015).
Sharing Clinical Reports Project (SCRP) RCV000031565 SCV000054170 pathogenic Breast-ovarian cancer, familial 2 2011-08-19 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031565 SCV000146653 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Division Human Genetics,Medical University Innsbruck RCV000031565 SCV000212022 pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000167830 SCV000587784 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031565 SCV000733269 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735569 SCV000863707 pathogenic Breast and/or ovarian cancer 2004-02-13 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785224 SCV000923792 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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