ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3975_3978dup (p.Ala1327fs) (rs397515636)

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Total submissions: 12
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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) RCV000210997 SCV000300692 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 RCV000044327 SCV000072340 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala1327Cysfs*4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with breast cancer (PMID: 10978364, 20104584) and in families affected with breast and ovarian cancer (PMID: 25366421, 25066507, 16168118, 22923021). It is also known as 4206insTGCT in the literature. ClinVar contains an entry for this variant (Variation ID: 51578). 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 RCV000129632 SCV000184425 pathogenic Hereditary cancer-predisposing syndrome 2017-10-04 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)
Michigan Medical Genetics Laboratories,University of Michigan RCV000210997 SCV000267763 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000210997 SCV000296573 pathogenic Breast-ovarian cancer, familial 2 2016-01-28 criteria provided, single submitter clinical testing
GeneKor MSA RCV000238801 SCV000296821 pathogenic Familial cancer of breast 2018-08-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000210997 SCV000326951 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000486384 SCV000566285 pathogenic not provided 2018-05-31 criteria provided, single submitter clinical testing This duplication of 4 nucleotides in BRCA2 is denoted c.3975_3978dupTGCT at the cDNA level and p.Ala1327CysfsX4 (A1327CfsX4) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is ATAC[dupTGCT]GCCA. The duplication causes a frameshift, which changes an Alanine to a Cysteine at codon 1327, 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.3975_3978dupTGCT, previously reported as BRCA2 4203_4206dupTGCT, BRCA2 3978insTGCT and BRCA2 4206insTGCT, has been observed in multiple individuals and families with Hereditary Breast and Ovarian Cancer (Plaschke 2000, Lubinski 2004, Pohlreich 2005, Borg 2010, Stegel 2011, Zhang 2011, Novakovic 2012, Karami 2013, Janavicius 2014, Krajc 2014, Ratajska 2015). We consider this variant to be pathogenic.
Color RCV000129632 SCV000683594 pathogenic Hereditary cancer-predisposing syndrome 2015-04-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044327 SCV000694733 pathogenic Hereditary breast and ovarian cancer syndrome 2016-09-01 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3975_3978dupTGCT (p.Ala1327Cysfs) 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.4092_4093delAT/p.Ile1364fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/103404 control chromosomes at a frequency of 0.0000097, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant was reported in numerous affected individuals in the literature and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000210997 SCV000839906 pathogenic Breast-ovarian cancer, familial 2 2017-04-03 criteria provided, single submitter clinical testing This c.3975_3978dup (p.Ala1327Cysfs*4) has previously been reported in at least two patients from two cohorts of 134 and 40 patients respectively [PMID 25366421, 10978364, reported as 4206insTGCT in the latter]. The c.3975_3978dup (p.Ala1327Cysfs*4) variant has been observed in one European (Non Finnish) individual at the heterozygous state in the ExAC database (http://exac.broadinstitute.org/variant/13-32912466-C-CTGCT). This 4 bp duplication is located in exon 11, and leads to the creation of a frameshift and a premature stop codon at amino acid position 1330 of the BRCA2 protein. It is thus classified as pathogenic. This variant is also considered medically actionable [ACMG59, PMID 27854360].
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044327 SCV000587692 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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