Submissions for variant NM_007294.4(BRCA1):c.2241del (p.Asp749fs)

dbSNP: rs80357650

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)	RCV000077512	SCV000299729	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000077512	SCV000296425	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-02-06	criteria provided, single submitter	clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077512	SCV000325304	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496653	SCV000698932	pathogenic	Hereditary breast ovarian cancer syndrome	2016-03-01	criteria provided, single submitter	clinical testing	Variant summary: The c.2241delC variant leads to premature termination codon, predicted to cause a truncated or absent BRCA1 protein, which is a commonly known mechanism for disease. Truncations downstream of this position (e.g.c.2411_2412delAG, c.2475delC) have been classified internally as pathogenic. This variant is not found in 121378 control chromosomes, however, it has been reported in several breast cancer patients. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Invitae	RCV000496653	SCV001592115	pathogenic	Hereditary breast ovarian cancer syndrome	2020-08-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant has been reported in a family affected with breast and/or ovarian cancer (PMID: 16758124). This variant is also known as c.2360delC in the literature. ClinVar contains an entry for this variant (Variation ID: 54510). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asp749Ilefs*4) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product.
GeneDx	RCV001565131	SCV001788414	pathogenic	not provided	2019-10-28	criteria provided, single submitter	clinical testing	Frameshift 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; Observed in individuals with a personal or family history including breast and ovarian cancers (Infante et al., 2006; Gardner et al., 2018; Mehta et al., 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek et al., 2016); Also known as 2360delC; This variant is associated with the following publications: (PMID: 29308099, 16758124, 30555256)
Sema4, Sema4	RCV002257393	SCV002538106	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-19	criteria provided, single submitter	curation
Ambry Genetics	RCV002257393	SCV002725486	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	clinical testing	The c.2241delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2241, causing a translational frameshift with a predicted alternate stop codon (p.D749Ifs*4). This alteration was identified in a cohort of 206 unrelated breast and/or ovarian cancer cases from North India who met NCCN guidelines for genetic testing (Mehta A et al. Cancer Manag Res, 2018 Dec;10:6505-6516). 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.
Sharing Clinical Reports Project (SCRP)	RCV000077512	SCV000109312	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2011-07-26	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077512	SCV000144353	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1998-07-10	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496653	SCV000587201	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000077512	SCV000591374	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The p.Asp749IlefsX4 deletion variant has been previously reported in the literature in 1 of 528 proband chromosomes in an individual with breast and ovarian cancer (Infante 2006). The p.Asp749IlefsX4 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 749 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in 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. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as pathogenic.