ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3167_3170del (p.Gln1056fs) (rs80359372)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561663 SCV000665939 pathogenic Hereditary cancer-predisposing syndrome 2016-12-08 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) RCV000113141 SCV000146182 pathogenic Breast-ovarian cancer, familial 2 2001-10-29 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113141 SCV000326824 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000113141 SCV000488268 likely pathogenic Breast-ovarian cancer, familial 2 2016-02-09 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113141 SCV000300592 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 RCV000497277 SCV000210734 pathogenic not provided 2017-10-23 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.3167_3170delAAAA at the cDNA level and p.Gln1056ArgfsX3 (Q1056RfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AATC[delAAAA]GAAA. The deletion causes a frameshift, changing a Glutamine to an Arginine at codon 1056, and creating a premature stop codon at position 3 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 3167_3170delAAAA, also described as BRCA2 3395del4 or 3395_3398delAAAA using alternate nomenclature, has been published in association with Hereditary Breast and Ovarian Cancer syndrome (Lubinski 2004, Zhang 2012) and is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000496382 SCV000917040 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-15 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3167_3170delAAAA (p.Gln1056ArgfsX3) 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. The variant allele was found at a frequency of 4.1e-06 in 241872 control chromosomes (gnomAD). c.3167_3170delAAAA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lubinski 2004, Palma 2008, Susswein 2015, Sun 2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (5x) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000496382 SCV000964140 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.Gln1056Argfs*3) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs80359372, ExAC 0.01%). This variant has been reported in the literature in individuals affected with breast or ovarian cancer (PMID: 26187060, 26681312, 18703817, 28724667), and also in a family with undefined cancer (PMID: 15131399). This variant is also known as 3395del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 51413). 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 RCV000496382 SCV000605817 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-27 criteria provided, single submitter clinical testing The p.Gln1056fs variant in BRCA2 has been identified in at least 5 individuals w ith BRCA2-associated cancers (Lubinski 2004, Palma 2008, Susswein 2015, Breast C ancer Information Core (BIC)database). This variant has also been identified in 1/17212 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org/; dbSNP rs80359372). Please note that this frequency is low enough to be consistent with the frequency of hereditary breast and ovar ian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positi on 1056 and leads to a premature termination codon 3 amino acids downstream. Thi s alteration is then predicted to lead to a truncated or absent protein. Heteroz ygous loss of function of the BRCA2 gene is an established disease mechanism in individuals with HBOC. In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV00030 0592.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000497277 SCV000887782 pathogenic not provided 2017-11-09 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496382 SCV000587661 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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