ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3847_3848del (p.Val1283fs) (rs80359405)

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Total submissions: 27
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131095 SCV000186025 pathogenic Hereditary cancer-predisposing syndrome 2017-04-25 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 RCV000160281 SCV000541010 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031440 SCV000146307 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770721 SCV000902200 pathogenic Breast and/or ovarian cancer 2017-03-07 criteria provided, single submitter clinical testing
Color RCV000131095 SCV000683584 pathogenic Hereditary cancer-predisposing syndrome 2016-06-15 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031440 SCV000326923 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031440 SCV000220629 pathogenic Breast-ovarian cancer, familial 2 2014-08-25 criteria provided, single submitter literature only
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031440 SCV000744446 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000031440 SCV000605697 pathogenic Breast-ovarian cancer, familial 2 2016-09-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044280 SCV000591878 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031440 SCV000733250 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Division Human Genetics,Medical University Innsbruck RCV000031440 SCV000212018 pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000505838 SCV000708829 pathogenic not provided 2017-05-30 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031440 SCV000282384 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000160281 SCV000210739 pathogenic Familial cancer of breast 2014-09-16 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3847_3848delGT at the cDNA level and p.Val1283LysfsX2 (V1283KfsX2) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AACT{delGT}AAGT. The deletion causes a frameshift, which changes a Valine to a Lysine at codon 1283 in exon 11, and creates a premature stop codon at position 2 of the new reading frame. This mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.3847_3848delGT, previously reported as 4075delGT, has been reported in association with breast and ovarian cancer (Tavtigian 1996). BRCA2 c.3847_3848delGT is also a common mutation in Norwegian and Danish populations (Janavicius 2010). We therefore consider this mutation to be pathogenic. and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. The predominant BRCA2-related cancer risks for women who have not been diagnosed with cancer have been estimated as 41% - 84% lifetime risk for breast cancer and 11% - 27% lifetime risk for ovarian cancer (Ford 1998, Risch 2006). BRCA2 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Biron-Shental 2006). Women with BRCA1/2 mutations also have an increased risk for contralateral breast cancer. Women with BRCA mutations whose first cancer was diagnosed under age 40 have a 21-31% risk to develop a second breast cancer within 10 years and a 63% risk to develop a second breast cancer within 25 years. Women with BRCA mutations whose first cancer was diagnosed between ages 40 and 50 have an 11-13% risk to develop a second breast cancer within 10 years and a 44-49% risk within 25 years. Women with BRCA mutations whose first cancer was diagnosed after age 50 have an 8% risk to develop a second breast cancer within 10 years and a 20% risk within 25 years (Graeser 2009). Other cancer risks associated with a BRCA2 mutation include up to a 7% risk for pancreatic cancer (Ozcelik 1997, The Breast Cancer Linkage Consortium 1999), up to a 34% risk for prostate cancer in male carriers (Thompson 2001), and up to a 7% risk for male breast cancer (Liede 2004). The variant is found in BRCA,HIRISK-BR-HEREDIC,BR-OV-HEREDIC panel(s).
GeneKor MSA RCV000505838 SCV000693565 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031440 SCV000743291 pathogenic Breast-ovarian cancer, familial 2 2014-10-10 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785219 SCV000923787 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000031440 SCV000993558 pathogenic Breast-ovarian cancer, familial 2 2019-02-21 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000031440 SCV000839910 pathogenic Breast-ovarian cancer, familial 2 2017-04-04 criteria provided, single submitter clinical testing The c.3847_3848del (p.Val1283Lysfs*2) variant has been detected in several patients and families with breast and/or ovarian cancer [PMID 8589730, 22752604, 24504028, 22006311, 21324516, sometimes reported as 4075delGT], colorectal cancer [PMID 24814045] and prostate cancer [PMID 21952622]. This variant has been reported in 11 heterozygous individuals from the ExAC population database (http://exac.broadinstitute.org/variant/13-32912337-CTG-C). This 2 bp deletion is located in exon 11, and leads to the creation of a frameshift and a premature stop codon at amino acid position. This variant is expected to result in a loss of function of the protein and is thus classified as pathogenic. This pathogenic variant in the BRCA2 gene is also considered medically actionable [ACMG59, PMID 27854360]
Integrated Genetics/Laboratory Corporation of America RCV000044280 SCV000694724 pathogenic Hereditary breast and ovarian cancer syndrome 2015-06-22 criteria provided, single submitter clinical testing Variant summary: This frameshift variant leads to premature truncation at exon 11. In ExAC, it has been observed at allele frequency of 11/94102 chromosomes. This frequency is lower than the maximal expected allele frequency for a pathogenic BRCA2 variant based on the disease prevalence of HBOC. It has been recurrently observed in patients with HBOC. This supports that the 11 individuals with this variant in ExAC are very likely to represent as subclinical cases and/or reduced penetrance. Multiple labs (via ClinVar) classify the variant as pathogenic. Therefore, based on the variant's nature and location, and population and patient data, this has been classified as Pathogenic.
Invitae RCV000044280 SCV000072293 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.Val1283Lysfs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs746229647, ExAC 0.02%). This variant has been reported in several individuals and families affected with breast, ovarian, and prostate cancer (PMID: 8589730, 21324516, 23199084, 21952622). It was also shown to segregate with disease in a family with colorectal and other cancers (PMID: 24814045). This variant is also known as 4075delGT in the literature. ClinVar contains an entry for this variant (Variation ID: 37859). 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 RCV000044280 SCV000271326 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-08 criteria provided, single submitter clinical testing The p.Val1283fs variant in BRCA2 has been reported in >35 individuals with BRCA2 -associated cancers (Wang 2012, Breast Cancer Information Core (BIC) database). This variant has also been identified in 11/50346 European chromosomes by the Ex ome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs803594 05); however, this frequency is low enough to be consistent with the frequency o f hereditary breast and ovarian cancer (HBOC) in the general population. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1283 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncate d or absent protein. Heterozygous loss of function of the BRCA2 gene is an estab lished disease mechanism for HBOC. In summary, this variant meets our criteria t o be classified as pathogenic for HBOC in an autosomal dominant manner based upo n the predicted impact to the protein.
Michigan Medical Genetics Laboratories,University of Michigan RCV000031440 SCV000267761 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505838 SCV000296700 pathogenic not provided 2015-03-20 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044280 SCV000587682 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031440 SCV000054045 pathogenic Breast-ovarian cancer, familial 2 2013-05-31 no assertion criteria provided clinical testing

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