Submissions for variant NM_007294.4(BRCA1):c.1360_1361del (p.Glu453_Ser454insTer)

dbSNP: rs80357969

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000030987	SCV000299586	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456126	SCV000075453	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser454*) 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 present in population databases (rs80357969, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10528853, 22874498, 26219728, 26681312). This variant is also known as 1479delAG. ClinVar contains an entry for this variant (Variation ID: 37406). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131838	SCV000186893	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-16	criteria provided, single submitter	clinical testing	The c.1360_1361delAG pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 1360 to 1361, causing a translational frameshift with a predicted alternate stop codon (p.S454*). This alteration has been reported in several unrelated individuals diagnosed with breast and/or ovarian cancer (van Orsouw NJ et al. J. Med. Genet. 1999 Oct;36(10):747-53; Ottini L et al. Breast Cancer Res. 2000 Mar;2(4):307-10; Risch HA et al. J. Natl. Cancer Inst. 2006 Dec 6;98(23):1694-706; Ozcelik H et al. J. Mol. Diagn. 2012 Sep;14(5):467-75; Azzollini J et al. Eur. J. Intern. Med. 2016 Jul;32:65-71; Plaskocinska I et al. J. Med. Genet. 2016 Oct;53(10):655-61; Heramb C et al. Hered. Cancer Clin. Pract. 2018 Jan;16:3). Of note, this alteration is also designated as 1479delAG in published literature. 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.
GeneDx	RCV000047440	SCV000210012	pathogenic	not provided	2020-11-10	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; Reported in association with breast and ovarian cancer (Ottini 2000, Zhang 2011); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also know as c.1479_1480delAG; 1479delAG; This variant is associated with the following publications: (PMID: 31447099, 10528853, 21324516, 11179017, 28087643, 11056688, 22874498, 26681312, 17148771, 27062684, 29339979, 30720243)
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000030987	SCV000325047	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000030987	SCV000564354	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-01-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000047440	SCV000600249	pathogenic	not provided	2021-03-25	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BRCA1 protein synthesis. In addition, it has been reported in individual and families with breast and ovarian cancer in the published literature (PMID: 31209999 (2019), 26219728 (2016), 11056688 (2000)). Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131838	SCV000688334	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant is also known as 1479delAG based on Breast Cancer Information Core (BIC) nomenclature. This variant has been reported in over twenty individuals affected with breast and/or ovarian cancer, and in high-risk breast and ovarian cancer families (PMID: 10528853, 11056688, 11938448, 17148771, 21324516, 22874498, 26219728, 26681312, 27208206, 32245699, 32438681, 33403015, 33471991). This variant has been identified in 29 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 2/251004 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 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	RCV000456126	SCV000698854	pathogenic	Hereditary breast ovarian cancer syndrome	2016-12-09	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.1360_1361delAG (p.Ser454Terfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121340 (1/60670), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. The variant of interest was reported in multiple affected individuals via publications. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "Pathogenic."
Mendelics	RCV000456126	SCV000839286	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000030987	SCV001434998	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2018-10-12	criteria provided, single submitter	clinical testing	The c.1360_1361delAG (p.Ser454*) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple patients with hereditary breast and ovarian cancer (PMID 10528853, 11056688, 17148771), and has been reported 19 times in Breast Cancer Information Core. This variant is observed at a low minor allele frequency (2/245828) in gnomAD. Therefore, the c.1360_1361delAG (p.Ser454*) variant in the BRCA1 gene is classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000047440	SCV001449758	pathogenic	not provided	2014-06-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000047440	SCV003809147	pathogenic	not provided	2021-11-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000030987	SCV004212690	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-10-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492307	SCV004240216	pathogenic	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000047440	SCV005197274	pathogenic	not provided	2024-02-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000047440	SCV005890919	pathogenic	not provided	2024-12-01	criteria provided, single submitter	clinical testing	BRCA1: PVS1, PM2, PS4:Moderate
Sharing Clinical Reports Project (SCRP)	RCV000030987	SCV000053579	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000030987	SCV000144066	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000456126	SCV000587124	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000030987	SCV000591325	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Ser454X variant was identified in at least 5 of 112950 proband chromosomes (frequency: 0.00004) from individuals or families with hereditary breast or ovarian cancer (Judkins 2005, Ottini 2000, Risch 2001, van Orsouw 1999). The variant was also previously identified by our laboratory in 1 individual with breast and ovarian cancer. The variant was identified in dbSNP (ID: rs80357969) “With Pathogenic allele”, and the BIC database (19X as Pathogenic). The p.Ser454X variant leads to a premature stop codon at position 454, 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.
BRCAlab, Lund University	RCV000030987	SCV002589080	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-08-26	no assertion criteria provided	clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000030987	SCV005061277	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2021-05-24	no assertion criteria provided	case-control