ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.658_659del (p.Val220fs) (rs80359604)

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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000074548 SCV000883510 pathogenic not provided 2017-09-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131858 SCV000186913 pathogenic Hereditary cancer-predisposing syndrome 2017-10-31 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 RCV000466729 SCV000540998 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031637 SCV000147427 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131858 SCV000292146 pathogenic Hereditary cancer-predisposing syndrome 2016-08-15 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031637 SCV000327465 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031637 SCV000221117 pathogenic Breast-ovarian cancer, familial 2 2015-02-04 criteria provided, single submitter literature only
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031637 SCV000744390 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Department of Medical Genetics,Oslo University Hospital RCV000031637 SCV000605688 pathogenic Breast-ovarian cancer, familial 2 2015-10-06 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031637 SCV000733216 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031637 SCV000282430 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 RCV000735587 SCV000863725 pathogenic Breast and/or ovarian cancer 2016-12-04 no assertion criteria provided clinical testing
GeneDx RCV000074548 SCV000108633 pathogenic not provided 2017-01-24 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.658_659delGT at the cDNA level and p.Val220IlefsX4 (V220IfsX4) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AACT[delGT]ATTT. The deletion causes a frameshift, which changes a Valine to an Isoleucine at codon 220, and creates a premature stop codon at position 4 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.658_659delGT, previously reported as 886delGT using alternate nomenclature, has been reported in multiple individuals from hereditary breast and ovarian cancer families (Frank 1998, Jakubowska 2003, Machado 2007, Berzina 2013, Cunningham 2014, de Juan 2015) and has been observed in the compound heterozygous state with a second pathogenic BRCA2 variant in patients with Fanconi anemia (Alter 2007, Miele 2015). Based on currently available evidence, we consider this variant to be pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000031637 SCV000584073 pathogenic Breast-ovarian cancer, familial 2 2014-07-10 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV000044988 SCV000494408 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-18 criteria provided, single submitter clinical testing Variant summary: The c.658_659delGT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.755_758delACAG, p.Asp252fsX24; c.771_775delTCAAA, p.Asn257fsX17; c.778_779delGA, p.Glu260fsX15). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.006% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been reported in numerous affected individuals in the literature, including 2 siblings affected with Fanconi anemia who also carried a second pathogenic BRCA2 variant (Svojgr_2016). Mutliple reputable clinical labs have classified the variant as "Pathogenic". Taken together, this variant is classified as pathogenic.
Invitae RCV000044988 SCV000073001 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val220Ilefs*4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs768580992, ExAC 0.01%). This variant has been reported in individuals affected with hereditary breast and ovarian cancer (PMID: 9667259, 22923021, 23767878, 24504028), and Fanconi anemia (PMID: 26657402). This variant is also known as 886delGT in the literature. ClinVar contains an entry for this variant (Variation ID: 9342). 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 RCV000044988 SCV000605780 pathogenic Hereditary breast and ovarian cancer syndrome 2015-04-17 criteria provided, single submitter clinical testing The p.Val220fs variant in BRCA2 has been identified in >50 individuals with BRCA 2-associated cancers (Frank 1998, Berzina 2013, Breast Cancer Information Core ( BIC) database) and in 3 compound heterozygous individuals with Fanconi anemia (O ffit 2003, Hirsch 2004, Reid 2005). This variant has been identified in 4/51064 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs80359604). This variant is predicted to cause a frame shift, which alters the protein?s amino acid sequence beginning at position 220 and leads to a premature termination codon 4 amino acids downstream. This altera tion is then predicted to lead to a truncated or absent protein. In summary, thi s variant meets our criteria to be classified as pathogenic for hereditary breas t and ovarian cancer in an autosomal dominant manner based on the low frequency in controls and the predicted impact to the protein.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000074548 SCV000778635 pathogenic not provided 2016-12-27 no assertion criteria provided clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000031637 SCV000195951 pathogenic Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
OMIM RCV000009929 SCV000030150 pathogenic Fanconi anemia, complementation group D1 2007-01-01 no assertion criteria provided literature only
OMIM RCV000009930 SCV000030151 pathogenic Wilms tumor 1 2007-01-01 no assertion criteria provided literature only
OMIM RCV000009931 SCV000030152 risk factor Glioma susceptibility 3 2007-01-01 no assertion criteria provided literature only
OMIM RCV000009932 SCV000030153 pathogenic Medulloblastoma 2007-01-01 no assertion criteria provided literature only
PreventionGenetics RCV000074548 SCV000805748 pathogenic not provided 2014-09-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074548 SCV000296738 pathogenic not provided 2015-02-06 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044988 SCV000587560 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031637 SCV000054244 pathogenic Breast-ovarian cancer, familial 2 2014-01-04 no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000210073 SCV000266043 pathogenic Breast-ovarian cancer, familial 1 2015-11-20 criteria provided, single submitter clinical testing

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