Submissions for variant NM_000059.4(BRCA2):c.7681C>T (p.Gln2561Ter)

dbSNP: rs80358994

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000083140	SCV000301191	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	RCV000083140	SCV000327715	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507834	SCV000602784	pathogenic	not specified	2016-11-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000773271	SCV000906939	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 16 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	RCV000496838	SCV001589156	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln2561*) 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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 52386). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000496838	SCV001653095	pathogenic	Hereditary breast ovarian cancer syndrome	2019-02-08	criteria provided, single submitter	clinical testing	The p.Gln2561X variant in BRCA2 has been previously reported in at least 4 individuals with BRCA2-associated cancers (Breast Information Core Database; https://research.nhgri.nih.gov/bic/, Rizzolo 2017) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 2561 which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer (HBOC). Moreover, this variant was classified as pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000301191.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_supporting.
Ambry Genetics	RCV000773271	SCV002673567	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-27	criteria provided, single submitter	clinical testing	The p.Q2561* pathogenic mutation (also known as c.7681C>T), located in coding exon 15 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7681. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This alteration has been identified in numerous breast and/or ovarian cancer families worldwide (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Yadav S et al. J Clin Oncol, 2020 05;38:1409-1418; Incorvaia L et al. Ther Adv Med Oncol, 2020 Dec;12:1758835920975326; Incorvaia L et al. Cancers (Basel), 2020 May;12). 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.
Baylor Genetics	RCV003460612	SCV004214574	pathogenic	Familial cancer of breast	2021-05-25	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083140	SCV000115214	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083140	SCV000147161	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496838	SCV000587903	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research