ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4284dup (p.Gln1429fs) (rs80359439)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130074 SCV000184901 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)
Breast Cancer Information Core (BIC) (BRCA2) RCV000031473 SCV000146401 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000130074 SCV000292168 pathogenic Hereditary cancer-predisposing syndrome 2015-07-21 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031473 SCV000327007 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031473 SCV000220993 likely pathogenic Breast-ovarian cancer, familial 2 2014-12-29 criteria provided, single submitter literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044387 SCV000591899 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-21 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031473 SCV000300733 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000160287 SCV000210748 pathogenic not provided 2019-01-17 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.4284dupT at the cDNA level and p.Gln1429SerfsX9 (Q1429SfsX9) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ATTTTT[dupT]CAGA. The duplication causes a frameshift, which changes a Glutamine to a Serine at codon 1429, and creates a premature stop codon at position 9 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.4284dupT, previously reported as 4510insT or 4512insT using alternate nomenclature, has been observed in association with breast and ovarian cancer (Risch 2001, Zuradelli 2010, Koumpis 2011, Song 2014, Tea 2014). We consider this variant to be pathogenic.
GeneKor MSA RCV000044387 SCV000693567 pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-01 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000031473 SCV000839927 pathogenic Breast-ovarian cancer, familial 2 2018-01-30 criteria provided, single submitter clinical testing This c.4284_4285insT (p.Gln1429Serfs*9) variant in the BRCA2 gene has been reported in multiple breast cancer and ovarian cancer patient [PMID: 21120943, 22085629, 24728189] while only observed once in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidences, this c.4284_4285insT (p.Gln1429Serfs*9) variant in the BRCA2 gene is classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000044387 SCV000694762 pathogenic Hereditary breast and ovarian cancer syndrome 2017-03-07 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4284dupT (p.Gln1429Serfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.4398_4402delACATT [p.Leu1466fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent from the large control population database ExAC (0/122560 control chromosomes). Several publications have identified the variant in affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases have cited this variant in patients and have classified it as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000044387 SCV000072400 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1429Serfs*9) 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 reported in individuals affected with breast and ovarian cancer (PMID: 11179017, 20373018, 22085629, 24156927, 24728189). This variant is also known as 4510insT and 4512insT in the literature. ClinVar contains an entry for this variant (Variation ID: 37892). 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 RCV000044387 SCV000271327 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-08 criteria provided, single submitter clinical testing The p.Gln1429fs variant in BRCA2 has been reported in >10 individuals with BRCA2 -associated cancers (Risch 2001, Zuradelli 2010, Zhang 2011, Koumpis 2011, Caux- Moncoutier 2011, Song 2014, Breast Cancer Information Core (BIC) database) and w as absent from large population studies. This variant is predicted to cause a fr ameshift, which alters the protein?s amino acid sequence beginning at position 1 429 and leads to a premature termination codon 9 amino acids downstream. This al teration is then predicted to lead to a truncated or absent protein. Heterozygou s loss of function of the BRCA2 gene is an established disease mechanism in here ditary breast and ovarian cancer (HBOC). In addition, this variant was classifie d as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Clin Var SCV000300733.2). In summary, this variant meets our criteria to be classifie d as pathogenic for HBOC in an autosomal dominant manner.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160287 SCV000296728 pathogenic not provided 2015-02-20 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044387 SCV000587708 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031473 SCV000054078 pathogenic Breast-ovarian cancer, familial 2 2012-10-30 no assertion criteria provided clinical testing

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