ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6644_6647del (p.Tyr2215fs) (rs80359616)

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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) RCV000031642 SCV000301085 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 RCV000416517 SCV000073019 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr2215Serfs*13) 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 observed in individuals affected with breast and/or ovarian cancer (PMID: 9150172, 22144684, 21324516, 16683254, 21120943). This variant is also known as 6872del4 or 6872delACTC in the literature. ClinVar contains an entry for this variant (Variation ID: 38060). 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 RCV000131027 SCV000185957 pathogenic Hereditary cancer-predisposing syndrome 2018-03-01 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000219562 SCV000278871 pathogenic not provided 2017-07-26 criteria provided, single submitter clinical testing This deletion of 4 nucleotides in BRCA2 is denoted c.6644_6647delACTC at the cDNA level and p.Tyr2215SerfsX13 (Y2215SfsX13) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACTT[delACTC]CAAA. The deletion causes a frameshift, which changes a Tyrosine to a Serine at codon 2215, and creates a premature stop codon at position 13 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.6644_6647delACTC, previously reported as 6872_6875delACTC and 6872del4, has been reported in association with breast and ovarian cancer and is considered to be pathogenic (Serova-Sinilnikova 1997, Verhoog 2001, Lewis 2006, Zhang 2011, Caputo 2012, Tung 2015).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031642 SCV000296668 pathogenic Breast-ovarian cancer, familial 2 2015-05-12 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031642 SCV000327483 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000416517 SCV000494433 pathogenic Hereditary breast and ovarian cancer syndrome 2019-03-05 criteria provided, single submitter clinical testing Variant summary: The variant, BRCA2 c.6644_6647delACTC (p.Tyr2215SerfsX13) 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 (eg. c.6682dupG(p.Val2228fsX5), c.6757_6758delCT(p.Leu2253fsX7)). The variant allele was found at a frequency of 4.1e-06 in 244534 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with breast cancer, ovarian cancer and pancreatic cancer (Caputo_2012, Lee_2008, Hu_2018, Zhang_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507007 SCV000602786 pathogenic not specified 2016-10-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000416517 SCV000605813 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-27 criteria provided, single submitter clinical testing The p.Tyr2215fs variant in BRCA2 has been reported in >25 individuals with BRCA2 -associated cancers and segregated with disease in 5 relatives from 2 families ( Serova-Sinilnikova 1997, Caputo 2012, Zhang 2011, Risch 2001, Verhoog 2001, and Breast Cancer Information Core (BIC) database). It was also absent from large po pulation studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 2215 and leads to a prem ature termination codon 13 amino acids downstream. This alteration is then predi cted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovar ian cancer (HBOC). In addition, this variant was classified as Pathogenic on Sep tember 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000301085 .2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner.
Counsyl RCV000031642 SCV000677694 pathogenic Breast-ovarian cancer, familial 2 2017-04-18 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031642 SCV000744497 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000219562 SCV000889109 pathogenic not provided 2015-05-12 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769701 SCV000901119 pathogenic Breast and/or ovarian cancer 2017-05-26 criteria provided, single submitter clinical testing
Color RCV000131027 SCV000911346 pathogenic Hereditary cancer-predisposing syndrome 2017-12-23 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031642 SCV000054249 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031642 SCV000146900 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000416517 SCV000587863 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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