Submissions for variant NM_000059.4(BRCA2):c.4003G>T (p.Glu1335Ter)

dbSNP: rs747070579

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241203	SCV000300695	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	RCV000220552	SCV000277421	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-08	criteria provided, single submitter	clinical testing	The p.E1335* pathogenic mutation (also known as c.4003G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 4003. This changes the amino acid from a glutamic acid to a stop codon within coding exon 10. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768628	SCV000324879	likely pathogenic	Breast and/or ovarian cancer	2016-02-22	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241203	SCV000326956	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000257988	SCV000549841	pathogenic	Hereditary breast ovarian cancer syndrome	2024-07-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1335*) 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 (rs747070579, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29446198, 29470806). ClinVar contains an entry for this variant (Variation ID: 233112). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000220552	SCV000906073	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 11 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 has been identified in 1/230540 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.
Molecular Endocrinology Laboratory, Christian Medical College	RCV000241203	SCV002004018	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000257988	SCV002026096	pathogenic	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000257988	SCV000587693	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004725089	SCV005340759	pathogenic	BRCA2-related disorder	2024-06-26	no assertion criteria provided	clinical testing	The BRCA2 c.4003G>T variant is predicted to result in premature protein termination (p.Glu1335*). This variant has been reported in individuals with breast cancer (Singh et al. 2018. PubMed ID: 29470806; Rebbeck et al. 2018. PubMed ID: 29446198). This variant is reported in 0.0039% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in BRCA2 are expected to be pathogenic. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/233112/). This variant is interpreted as pathogenic.