Submissions for variant NM_000059.4(BRCA2):c.3226_3230del (p.Val1076fs)

dbSNP: rs397507659

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241468	SCV000300605	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000130009	SCV000184834	pathogenic	Hereditary cancer-predisposing syndrome	2014-01-08	criteria provided, single submitter	clinical testing	The c.3226_3230delGTAGT pathogenic mutation (also known as 3454del5) located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides between nucleotide positions 3226 and 3230, causing a translational frameshift with a predicted alternate stop codon. This mutation has been described in a hereditary breast and ovarian cancer (HBOC) family (Lubinski J et al. Fam. Cancer 2004 ;3(1):1-10). In addition to the clinical information presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241468	SCV000326837	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496926	SCV000694679	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3226_3230delGTAGT (p.Val1076CysfsX3) 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 was absent in 243162 control chromosomes. c.3226_3230delGTAGT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Lubinski_2004, van der Hout_2006). The following publications have been ascertained in the context of this evaluation (PMID: 15131399, 16683254). Three submitters including an expert panel (ENIGMA) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769691	SCV000901106	pathogenic	Breast and/or ovarian cancer	2017-08-17	criteria provided, single submitter	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496926	SCV000587666	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research