Submissions for variant NM_007294.4(BRCA1):c.3286C>T (p.Gln1096Ter)

dbSNP: rs80357485

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112045	SCV000299908	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	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	RCV000112045	SCV000325599	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000486625	SCV000568409	pathogenic	not provided	2020-05-22	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 in large population cohorts (Lek 2016); Also known as BRCA1 c.3405C>T; This variant is associated with the following publications: (PMID: 12181777, 15617999, 26083025, 25682074, 25525159, 25722380, 26187060, 28294317, 29446198, 30702160, 31825140, 32885271)
Ambry Genetics	RCV000510107	SCV000608080	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-27	criteria provided, single submitter	clinical testing	The p.Q1096* pathogenic mutation (also known as c.3286C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 3286. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in two individuals with a personal history of epithelial ovarian cancer and triple-negative breast cancer, respectively (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150(1):71-80; Majdak EJ et al. Eur. J. Cancer 2005 Jan;41(1):143-50). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386667	SCV001586992	pathogenic	Hereditary breast ovarian cancer syndrome	2021-06-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with breast and ovarian cancer (PMID: 15617999, 25682074, 27157322). ClinVar contains an entry for this variant (Variation ID: 54818). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln1096*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584).
MGZ Medical Genetics Center	RCV000112045	SCV002580349	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-10-01	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112045	SCV000144698	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356246	SCV001551361	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	BRCA1, EXON11, c.3286C>T, p.Gln1096X, Heterozygous, PathogenicrnThe BRCA1 p.Gln1096X variant was identified in 3 of 2880 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer and was not identified in 400 control chromosomes from healthy individuals (Liede 2002, Majdak 2005, Wong-Brown 2015). The variant was also identified in the following databases: dbSNP (ID: rs80357485) as "With Pathogenic allele", ClinVar (5x pathogenic), Clinvitae (2x pathogenic), LOVD 3.0 (1x), UMD-LSDB (1x causal), BIC Database (1x pathogenic), and ARUP Laboratories. The variant was not identified in the COGR, Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 1 of 245392 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 1 of 17248 chromosomes (freq: 0.00006), but not in the African, Ashkenazi Jewish, European (Finnish), European (Non-Finnish), Latino, Other, and South Asian populations. The c.3286C>T variant leads to a premature stop codon at position 1096 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000112045	SCV003927172	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	A known pathogenic mutation was detected in the BRCA1 gene (c.3286C>T). This sequence change creates a premature translational stop signal (p.Gln1096*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in gnomAD genomes. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 15617999, 25682074, 27157322). In-silico predictions show pathogenic computational verdict based on 5 pathogenic predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL and MutationTaster vs no benign predictions.This variant is also known as c.3405C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 54818) with 8 submissions all of which describe it as pathogenic, 3 stars, reviewed by expert panel. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332109	SCV004040521	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research