Submissions for variant NM_007294.4(BRCA1):c.1127del (p.Asn376fs)

dbSNP: rs80357821

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111557	SCV000299545	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.
Ambry Genetics	RCV000129494	SCV000184266	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-10	criteria provided, single submitter	clinical testing	The c.1127delA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1127, causing a translational frameshift with a predicted alternate stop codon (p.N376Ifs*18). This mutation has been described in multiple hereditary breast and ovarian cancer families (Arnold N et al. Hum. Mutat. 1999;14:333-9; Pohlreich P et al. Breast Cancer Res. 2005; 7:R728-36). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000505824	SCV000296324	pathogenic	not provided	2015-03-21	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111557	SCV000324963	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002451	SCV001160393	pathogenic	not specified	2019-03-13	criteria provided, single submitter	clinical testing	The BRCA1 c.1127delA; p.Asn376fs variant (rs80357821), also known as 1246delA using traditional nomenclature, is reported in the literature in several families affected with breast and/or ovarian cancer (Arnold 1999, Pohlreich 2005). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories and an expert panel in ClinVar (Variation ID: 54140). This variant causes a frameshift by deleting a single nucleotide, so it 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: Arnold N et al. A highly sensitive, fast, and economical technique for mutation analysis in hereditary breast and ovarian cancers. Hum Mutat. 1999;14(4):333-9. Pohlreich P et al. High proportion of recurrent germline mutations in the BRCA1 gene in breast and ovarian cancer patients from the Prague area. Breast Cancer Res. 2005;7(5):R728-36.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000111557	SCV001440861	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2019-01-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000505824	SCV001447226	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381195	SCV001579496	pathogenic	Hereditary breast ovarian cancer syndrome	2022-09-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54140). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 12181777, 16168118). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn376Ilefs*18) 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).
Revvity Omics, Revvity	RCV000505824	SCV003811788	pathogenic	not provided	2022-02-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000505824	SCV004035244	pathogenic	not provided	2023-09-19	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1
Baylor Genetics	RCV000111557	SCV004216859	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2022-12-28	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111557	SCV000144020	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785204	SCV000923772	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
CZECANCA consortium	RCV001270962	SCV001451766	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing