Submissions for variant NM_000059.4(BRCA2):c.4366G>T (p.Glu1456Ter)

dbSNP: rs876659847

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000257168	SCV000324237	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-10-18	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	RCV000257168	SCV000327018	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509662	SCV000607800	pathogenic	Hereditary cancer-predisposing syndrome	2022-04-19	criteria provided, single submitter	clinical testing	The p.E1456* pathogenic mutation (also known as c.4366G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 4366. This changes the amino acid from a glutamic acid to a stop codon within coding exon 10. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
GeneDx	RCV000657676	SCV000779425	pathogenic	not provided	2020-08-31	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal and/or family history of BRCA2-related cancers (Rebbeck 2018); Also known as 4594G>T; This variant is associated with the following publications: (PMID: 32856862, 29446198)
Color Diagnostics, LLC DBA Color Health	RCV000509662	SCV000905237	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 not been identified 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.
Invitae	RCV000496408	SCV000940017	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1456*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 266806). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000657676	SCV003816112	pathogenic	not provided	2022-08-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003475871	SCV004212876	pathogenic	Familial cancer of breast	2021-11-27	criteria provided, single submitter	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496408	SCV000587710	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research