Submissions for variant NM_007294.4(BRCA1):c.1450G>T (p.Gly484Ter)

dbSNP: rs80357304

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111620	SCV000299602	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	RCV000111620	SCV000325075	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000111620	SCV000564343	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-07-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284535	SCV001470374	pathogenic	not provided	2020-03-13	criteria provided, single submitter	clinical testing	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496826	SCV001587048	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly484*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 8807330, 29446198, 29470806). This variant is also known as c.1569G>T. ClinVar contains an entry for this variant (Variation ID: 54257). For these reasons, this variant has been classified as Pathogenic.
Molecular Endocrinology Laboratory, Christian Medical College	RCV000111620	SCV002003967	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002258786	SCV002538028	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-26	criteria provided, single submitter	curation
Ambry Genetics	RCV002258786	SCV002696870	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-23	criteria provided, single submitter	clinical testing	The p.G484* pathogenic mutation (also known as c.1450G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 1450. This changes the amino acid from a glycine to a stop codon within coding exon 9. This alteration, referred to as STOP484 (1569G>T), has been reported in the literature as a deleterious mutation (Couch FJ and Weber BL Hum. Mutat. 1996;8:8-18). This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in three families (Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3). 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.
New York Genome Center	RCV000111620	SCV003925118	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-05-11	criteria provided, single submitter	clinical testing	The c.1450G>T variant in BRCA1 has previously been in individuals with clinical features of familial breast and/or ovarian cancer [PMID: 30555256, 29339979,11199332, 29446198, 29470806] and it has been deposited in ClinVar [ClinVar ID: 54257] as Pathogenic. The c.1450G>T variant is observed in 1 allele (0.00037%minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.1450G>T variant in BRCA1 is located in exon 10 of this 23-exon gene, predicted to incorporate a premature termination codon (p.(Gly484Ter)), and is expected to result in loss-of-function via nonsense mediated decay. Multiple loss-of-function variants that are downstream to the c.1450G>T variant have been reported in the literature [PMID: 31528241] and ClinVar [ClinVar ID: 54264] in individuals with familial breast and/or ovarian cancer. Based on available evidence this c.1450G>T p.(Gly484Ter) variant identified in BRCA1 gene is classified as Pathogenic.
Baylor Genetics	RCV000111620	SCV005058259	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2024-02-02	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111620	SCV000144099	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2006-05-05	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496826	SCV000587136	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research