Submissions for variant NM_000059.4(BRCA2):c.274C>T (p.Gln92Ter)

dbSNP: rs80358529

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031380	SCV000300313	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.
GeneDx	RCV000212204	SCV000210448	pathogenic	not provided	2024-01-04	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 502C>T; This variant is associated with the following publications: (PMID: 27257965, 26843898, 32377563, 31825140, 31853058, 20104584, 25948282, 30287823)
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240677	SCV000265895	pathogenic	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Ambry Genetics	RCV000215800	SCV000278230	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-13	criteria provided, single submitter	clinical testing	The p.Q92* pathogenic mutation (also known as c.274C>T), located in coding exon 2 of the BRCA2 gene, results from a C to T substitution at nucleotide position 274. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This alteration was reported in a patient from a Polish cohort of women with early onset or familial breast and/or ovarian cancer (Kluska A et al. BMC Med Genomics, 2015 May;8:19). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000496410	SCV000591671	pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212204	SCV000600522	pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 30287823 (2018), 26843898 (2016), 25948282 (2015)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000215800	SCV001356465	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496410	SCV001572501	pathogenic	Hereditary breast ovarian cancer syndrome	2021-04-05	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.274C>T (p.Gln92X) 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 251214 control chromosomes. c.274C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Kluska_2015, Wojcik_2016, Zhang_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. Some submitters cite overlapping evidence utilized in the context of this evaluation. All submitters classified the variant as pathogenic in the germline and somatic settings. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496410	SCV001584863	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln92*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 37799). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212204	SCV004563572	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	The BRCA2 c.274C>T; p.Gln92Ter variant (rs80358529) is reported in the literature in individuals affected with or a family history of breast and/or ovarian cancer (Kluska 2015, Perez-Ibave 2023). This variant is reported in ClinVar (Variation ID: 37799). The p.Gln92Ter variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Kluska A et al. New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing. BMC Med Genomics. 2015 May 7;8:19. PMID: 25948282. Perez-Ibave DC et al. Identification of Germline Variants in Patients with Hereditary Cancer Syndromes in Northeast Mexico. Genes (Basel). 2023 Jan 28;14(2):341. PMID: 36833268.
Sharing Clinical Reports Project (SCRP)	RCV000031380	SCV000053985	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-16	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031380	SCV000146483	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	RCV000496410	SCV000587544	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research