Submissions for variant NM_000059.4(BRCA2):c.2905C>T (p.Gln969Ter)

dbSNP: rs886038080

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)	RCV000240967	SCV000300571	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	RCV000240967	SCV000326786	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550373	SCV000635254	pathogenic	Hereditary breast ovarian cancer syndrome	2024-08-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln969*) 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: 254509). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000550373	SCV000916975	pathogenic	Hereditary breast ovarian cancer syndrome	2017-12-28	criteria provided, single submitter	clinical testing	Variant summary: The c.2905C>T (p.Gln969*) variant in BRCA2 gene is a nonsense change that results in the loss of the ~2450 amino acids of BRCA2 protein (~72%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from control dataset of gnomAD (~244112 chrs). The variant is cited as Pathogenic by reputable databases/clinical laboratories. Taking together, the variant was classified as Pathogenic.
Ambry Genetics	RCV002436078	SCV002746850	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-21	criteria provided, single submitter	clinical testing	The p.Q969* pathogenic mutation (also known as c.2905C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2905. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This pathogenic mutation has been reported in multiple BRCA1/2 mutation positive individuals (Marchetti C et al. Ann Surg Oncol, 2018 Nov;25:3701-3708; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Concolino P et al. Int J Mol Sci, 2019 Jul;20; Klek S et al. JNCI Cancer Spectr, 2020 Jun;4:pkaa018; Santonocito C et al. Cancers (Basel), 2020 May;12). 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.
Color Diagnostics, LLC DBA Color Health	RCV002436078	SCV004361985	pathogenic	Hereditary cancer-predisposing syndrome	2022-07-11	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 reported in individuals affected with breast, ovarian, or endometrial cancer (PMID: 30128899, 31336956, 32596633). One of these individuals carried a second pathogenic variant in the BRCA2 gene that could explain the observed phenotype (PMID: 31336956). 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.
Fulgent Genetics, Fulgent Genetics	RCV005008217	SCV005633893	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer	2024-06-18	criteria provided, single submitter	clinical testing