Submissions for variant NM_007294.4(BRCA1):c.4945del (p.Arg1649fs)

dbSNP: rs80357655

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112431	SCV000300176	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.
GeneKor MSA	RCV000239002	SCV000296776	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This sequence change deletes one nucleotide from exon 15 of the BRCA1 mRNA (c.4945delA), causing a frameshift after codon 1649 and the creation of a premature translation stop signal 9 amino acid residues later p.(Arg1649Glufs*9). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. The mutation database ClinVar contains entries for this variant (Variation ID: 55328).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112431	SCV000326070	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579538	SCV000683229	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-21	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 15 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 has been reported in an individual affected with prostate cancer and suspected hereditary breast and ovarian cancer families (PMID: 10486320, 23569316, 29446198, 31209999). This variant has not been identified 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.
GeneDx	RCV000239002	SCV004170554	pathogenic	not provided	2023-10-26	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 personal and family history consistent with pathogenic variants in this gene (PMID: 10486320, 16287141, 23569316); Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5064delA; This variant is associated with the following publications: (PMID: 10486320, 16287141, 23569316)
Ambry Genetics	RCV000579538	SCV005026077	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-03	criteria provided, single submitter	clinical testing	The c.4945delA pathogenic mutation, located in coding exon 14 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4945, causing a translational frameshift with a predicted alternate stop codon (p.R1649Efs*9). This alteration has been identified in multiple individuals diagnosed with hereditary breast and/or ovarian cancer syndrome (HBOC) (Gayther SA et al. Am J Hum Genet, 1999 Oct;65:1021-9; Kroiss R et al. Hum Mutat, 2005 Dec;26:583-9; Ramus SJ et al. Hum Mutat, 2007 Dec;28:1207-15). Of note, this alteration is also known as 5061delA in published literature. 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112431	SCV000145218	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-06-21	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496397	SCV000587435	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785378	SCV000923949	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research