Submissions for variant NM_000059.4(BRCA2):c.36dup (p.Glu13Ter)

dbSNP: rs80359393

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000082917	SCV000300286	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000082917	SCV000326897	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000486380	SCV000566348	pathogenic	not provided	2015-04-22	criteria provided, single submitter	clinical testing	This duplication of one nucleotide is denoted BRCA2 c.36dupT at the cDNA level and p.Glu13Ter (E13X) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ATTTTT[T]GAAA. The duplication creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.36dupT, previously reported as 264dupT and 265insT using alternate nomenclature, has been observed in at least one family with hereditary breast cancer (Vaziri 2001). This variant is considered pathogenic.
Department of Pathology and Molecular Medicine, Queen's University	RCV000496400	SCV000588065	pathogenic	Hereditary breast ovarian cancer syndrome	2017-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182330	SCV001347760	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-31	criteria provided, single submitter	clinical testing	This variant duplicates 1 nucleotide in exon 2 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 265insT in the literature. This variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 11139249, 28692638, 29446198, 33471991). This variant has been identified in 1/31408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486380	SCV001469421	pathogenic	not provided	2020-07-03	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496400	SCV001584649	pathogenic	Hereditary breast ovarian cancer syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu13*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80359393, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 11139249, 29446198). This variant is also known as c.265insT. ClinVar contains an entry for this variant (Variation ID: 51509). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798232	SCV002043005	pathogenic	Breast and/or ovarian cancer	2019-08-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001182330	SCV002621307	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	The c.36dupT pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a duplication of T at nucleotide position 36, causing a translational frameshift with a predicted alternate stop codon (p.E13*). This pathogenic variant (referred to as 265insT) has been reported in one family with a strong history of breast cancer (Vaziri SA et al. Hum. Mutat. 2001;17:74). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496400	SCV004813723	pathogenic	Hereditary breast ovarian cancer syndrome	2024-02-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.36dupT (p.Glu13X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanismss for disease. The variant was absent in 251372 control chromosomes. c.36dupT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Gao_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31825140). ClinVar contains an entry for this variant (Variation ID: 51509). Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000082917	SCV000114991	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2008-07-15	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000082917	SCV000146041	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496400	SCV000587528	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research