Submissions for variant NM_000059.4(BRCA2):c.1261C>T (p.Gln421Ter)

dbSNP: rs80358419

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)	RCV000112900	SCV000300413	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	RCV000131850	SCV000186905	pathogenic	Hereditary cancer-predisposing syndrome	2025-03-11	criteria provided, single submitter	clinical testing	The p.Q421* pathogenic mutation (also known as c.1261C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1261. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in multiple high-risk breast and/or ovarian cancer cohorts (Kwong et al. Breast Cancer Res Treat. 2009 Oct;117(3):683-6; Kwong et al. PLoS One. 2012;7(9):e43994; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Huang KL et al. Cell, 2018 04;173:355-370.e14). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112900	SCV000326528	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496684	SCV000918929	pathogenic	Hereditary breast ovarian cancer syndrome	2018-06-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1261C>T (p.Gln421X) 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 (eg. c.1265delA (p.Asn422fsX8), c.1310_1313delAAGA (p.Lys437fsX22), and c.1456C>T (p.Gln486X)). The variant was absent in 240472 control chromosomes (gnomAD). The variant, c.1261C>T, has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Kwong_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496684	SCV001581184	pathogenic	Hereditary breast ovarian cancer syndrome	2021-05-25	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 19353265, 29446198). ClinVar contains an entry for this variant (Variation ID: 51092). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln421*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000496684	SCV002026065	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000112900	SCV004825855	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-15	criteria provided, single submitter	clinical testing	The c.1261C>T (p.Gln421*) variant in the BRCA2 gene is located on the exon 10 and introduces a premature translation termination codon (p.Gln421*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/prostate cancer (PMID: 31209999, 19353265, 35464868, 22970155, 31214711, 30287823). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 51092) and reviewed by the expert panel. This variant is absent in the general population database (gnomAD). Therefore, the c.1261C>T (p.Gln421*) variant of BRCA2 has been classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000112900	SCV000145842	not provided	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496684	SCV000587588	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Laboratory for Genotyping Development, RIKEN	RCV003162362	SCV002758122	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332097	SCV004040597	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research