ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1205del (p.Gly402fs) (rs397507265)

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Total submissions: 10
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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) RCV000031311 SCV000300406 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000129350 SCV000184114 pathogenic Hereditary cancer-predisposing syndrome 2015-10-12 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000160276 SCV000210729 pathogenic not provided 2016-03-14 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA2 is denoted c.1205delG at the cDNA level and p.Gly402ValfsX2 (G402VfsX2) at the protein level. The normal sequence, with the base that is deleted in braces, is TCAG[G]TCTA. The deletion causes a frameshift which changes a Glycine to a Valine at codon 402, and creates a premature stop codon at position 2 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. This variant, also reported as BRCA2 1433delG using alternate nomenclature, has been reported in individuals with personal and/or family histories consistent with Hereditary Breast and Ovarian Cancer (Nanda 2005, Churpek 2015, Lynce 2015). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031311 SCV000296589 pathogenic Breast-ovarian cancer, familial 2 2015-12-02 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031311 SCV000326514 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000496444 SCV000694520 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1205delG (p.Gly402Valfs) 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.1257delT, p.Cys419fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120776 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000496444 SCV000829725 pathogenic Hereditary breast and ovarian cancer syndrome 2018-04-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly402Valfs*2) 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 several individuals affected with breast and/or ovarian cancer (PMID: 25428789, 26250392,16234499). This variant is also known as 1433delG in the literature. ClinVar contains an entry for this variant (Variation ID: 37730). 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 RCV000496444 SCV000966962 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-13 criteria provided, single submitter clinical testing The p.Gly402ValfsX2 variant in BRCA2 has been reported in at least 3 African Ame rican individuals with a personal or family history of breast and/or ovarian can cer (Nanda 2005, Lynce 2015, Churpek 2015). This variant has been identified in 1/8734 African chromosomes by the Genome Aggregation Database (gnomAD, http://gn This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 402 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of functi on of the BRCA2 gene is an established disease mechanism in hereditary breast an d ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV00030040 6.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the presence in probands and th e predicted impact on the protein. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Sup porting.
Sharing Clinical Reports Project (SCRP) RCV000031311 SCV000053916 pathogenic Breast-ovarian cancer, familial 2 2008-03-11 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496444 SCV000587584 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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