ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2808_2811del (p.Ala938Profs) (rs80359351)

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Total submissions: 33
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000240755 SCV000492474 pathogenic Neoplasm of the breast criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000160273 SCV000885087 pathogenic not provided 2018-01-24 criteria provided, single submitter clinical testing The BRCA2 c.2808_2811delACAA variant (rs80359351) is reported in the literature in individuals affected with familial breast, ovarian and prostate cancers (Edwards 2010, Kote-Jarai 2011, Walsh 2011, Wooster 1995, Zhang 2011), and has been described as a founder variant in Western Europeans (Caputo 2012). This variant is reported as pathogenic 23 times in ClinVar (Variation ID: 9322) and is seen in the general population at a low overall frequency of 0.001% (3/245804 alleles) in the Genome Aggregation Database. This variant deletes 4 nucleotides causing a frameshift, and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, this variant is considered pathogenic. References: Caputo S et al. (2012) Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res. 40(Database issue):D992-1002. Edwards SM et al. (2010) Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 103(6):918-24. Kote-Jarai Z et al. (2011) BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 105(8):1230-4. Walsh T et al. (2011) Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 108(44):18032-7. Wooster R et al. (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature. 378(6559):789-92. Zhang S et al. (2011) Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 121(2):353-7.
Ambry Genetics RCV000131102 SCV000186032 pathogenic Hereditary cancer-predisposing syndrome 2017-11-16 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)
Baylor Genetics RCV000458791 SCV000541011 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000009907 SCV000146117 pathogenic Breast-ovarian cancer, familial 2 2013-02-20 no assertion criteria provided clinical testing
Color RCV000131102 SCV000292132 pathogenic Hereditary cancer-predisposing syndrome 2015-04-05 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000009907 SCV000326768 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000009907 SCV000220481 pathogenic Breast-ovarian cancer, familial 2 2014-07-04 criteria provided, single submitter literature only
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000009907 SCV000744430 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000009907 SCV000605665 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044064 SCV000591826 pathogenic Hereditary breast and ovarian cancer syndrome 2012-05-06 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000044064 SCV000588085 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000009907 SCV000733240 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Division Human Genetics,Medical University Innsbruck RCV000009907 SCV000212014 pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000009907 SCV000282373 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735443 SCV000863579 pathogenic Breast and/or ovarian cancer 2016-03-29 no assertion criteria provided clinical testing
GeneDx RCV000160273 SCV000210725 pathogenic not provided 2018-11-16 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.2808_2811delACAA at the cDNA level and p.Ala938ProfsX21 (A938PfsX21) at the protein level, and is also known as 3034del4, 3036del4, or 3036_3039delACAA using alternate nomenclature. The normal sequence with the bases that are deleted in brackets is ATAA[delACAA]GCAA. The deletion causes a frameshift, changing an Alanine to a Proline at codon 938 and creating a premature stop codon at position 21 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.2808_2811delACAA has been reported in association with familial and early-onset breast and/or ovarian cancer (Wooster 1995, Salazar 2006, Walsh 2011, Zhang 2011, de Juan 2015), in individuals with prostate cancer (Kote-Jarai 2011, Edwards 2010), and as a recurrent variant in Western European and Hispanic populations (Diez 2003, Janavicius 2010, Caputo 2012, Ossa 2016). We consider this variant to be pathogenic.
GeneKor MSA RCV000160273 SCV000296818 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Genologica Medica RCV000009907 SCV000577950 pathogenic Breast-ovarian cancer, familial 2 2017-01-01 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000044064 SCV000607364 not provided Hereditary breast and ovarian cancer syndrome no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000009907 SCV000839926 pathogenic Breast-ovarian cancer, familial 2 2018-05-22 criteria provided, single submitter clinical testing The c.2808_2811delACAA (p.Ala938Profs*21) frameshift variant in BRCA2 is predicted to introduce a premature translation termination codon. It has been reported in multiple unrelated patients with breast, ovarian or prostate cancer [PMID 8524414, 22144684, 21952622, 22006311, 21324516]. This variant is classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000044064 SCV000694631 pathogenic Hereditary breast and ovarian cancer syndrome 2017-08-07 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.2808_2811delACAA (p.Ala938Profs) variant (legacy names: 3036del4 and 3036delACAA) 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. This variant is absent in 120732 control chromosomes from ExAC. This variant is known to be a one of the most common pathogenic variants in non-Ashkenazi Caucasians (Diez_2003, Caputo_2012, Hall_2009, Infante_2013). Several clinical diagnostic laboratories/reputable databases in ClinVar have classified this variant as pathogenic. Therefore, this variant is classified as pathogenic.
Invitae RCV000044064 SCV000072077 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala938Profs*21) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80359351, ExAC 0.003%). This variant has been reported in individuals affected with female breast cancer, male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer (PMID: 9585613, 21952622, 12955716, 23929434). In the literature, this variant is also known as 2807del4, 3034del4, 3036del4, 3034delAAAC, 3036delACAA, and 3036_3039del4. ClinVar contains an entry for this variant (Variation ID: 9322). 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 RCV000044064 SCV000271324 pathogenic Hereditary breast and ovarian cancer syndrome 2015-11-13 criteria provided, single submitter clinical testing The p.Ala938fs variant in BRCA2 is a well-established pathogenic variant for her editary breast and ovarian cancer (HBOC) and is one of the most common germline mutations in non-Ashkenazi Jewish individuals with breast cancer (Gao 2000, Diez 2003, Janavicius 2010, Caputo 2012, Kwong 2012, Infante 2013). This variant has also been identified in one male with prostate cancer and 5 males with breast c ancer (Edwards 2010, de Juan 2015). Furthermore, this variant was identified in 2/66388 European chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs80359351). The p.Ala938fs variant is predicted t o cause a frameshift, which alters the protein?s amino acid sequence beginning a t position 938 and leads to a premature termination codon 21 amino acids downstr eam. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mecha nism for HBOC. In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted imp act to the protein and prevalence in affected individuals.
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240755 SCV000265905 pathogenic Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000160273 SCV000778656 pathogenic not provided 2017-12-13 no assertion criteria provided clinical testing
Mendelics RCV000044064 SCV000838778 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000009907 SCV000267754 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
OMIM RCV000009907 SCV000030128 pathogenic Breast-ovarian cancer, familial 2 1995-12-21 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160273 SCV000296702 pathogenic not provided 2015-03-20 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044064 SCV000587644 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000009907 SCV000053988 pathogenic Breast-ovarian cancer, familial 2 2013-07-29 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000210161 SCV000266039 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing

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