Submissions for variant NM_000059.4(BRCA2):c.7738C>T (p.Gln2580Ter)

dbSNP: rs80358999

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113809	SCV000301199	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	RCV000113809	SCV000327721	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000496258	SCV000838861	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496258	SCV001591291	pathogenic	Hereditary breast ovarian cancer syndrome	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2580*) 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 ovarian cancer (PMID: 15868448, 28724667, 29446198, 29907814). ClinVar contains an entry for this variant (Variation ID: 52396). Studies have shown that this premature translational stop signal does not affect mRNA splicing (PMID: 29881398). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496258	SCV002500538	pathogenic	Hereditary breast ovarian cancer syndrome	2022-03-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7738C>T (p.Gln2580X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251416 control chromosomes. c.7738C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018, Vietri_2020, Zhang_2021, Pinto_2016). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113809	SCV000147168	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496258	SCV000587904	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research