Submissions for variant NM_007294.4(BRCA1):c.4391del (p.Pro1464fs)

dbSNP: rs80357916

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031170	SCV000300115	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	RCV000031170	SCV000325947	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022412	SCV001184144	pathogenic	Hereditary cancer-predisposing syndrome	2018-08-15	criteria provided, single submitter	clinical testing	The c.4391delC pathogenic mutation, located in coding exon 12 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4391, causing a translational frameshift with a predicted alternate stop codon (p.P1464Lfs*2). This mutation has been reported in individuals with breast cancer, triple negative breast cancer and fallopian tube cancer (Yazici H et al. Br. J. Cancer 2000 Sep;83:737-42; Laki F et al. Cancer 2007 May;109:1784-90; Vincent-Salomon A et al. Cancer Res. 2007 Jun;67:5134-40; Davies H et al. Nat. Med. 2017 Apr;23:517-525). Of note, this alteration is also designated as 4508delC and c.4389delC 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.
Color Diagnostics, LLC DBA Color Health	RCV001022412	SCV001345618	pathogenic	Hereditary cancer-predisposing syndrome	2020-02-12	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 13 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. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 15887246). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284549	SCV001470391	pathogenic	not provided	2020-04-16	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, 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.
Invitae	RCV001852620	SCV002229421	pathogenic	Hereditary breast ovarian cancer syndrome	2022-07-10	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: 37589). This variant is also known as 4508delC. This premature translational stop signal has been observed in individual(s) with personal and family history of breast and/or ovarian cancer (PMID: 10952777, 31954625, 32341426). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro1464Leufs*2) 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).
Sharing Clinical Reports Project (SCRP)	RCV000031170	SCV000053770	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-08-18	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000031170	SCV000145083	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001284549	SCV001551457	pathogenic	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Pro1464LeufsX2 variant was identified in 1 of 106 proband chromosomes (frequency: 0.009) from individuals or families with breast and ovarian cancer of Turkish ethnicity (Yazici 2000). The variant was also identified in dbSNP (ID: rs80357916) as with pathogenic allele: in the ClinVar and Clinvitae databases as pathogenic by ENIGMA, Consortium of Investigators of Modifiers of BRCA1/2, Sharing Clinical Reports Project and Breast Cancer Information Core. The variant was further identified in LOVD 3.0 database 2X with variant allele predicted to encode truncated non-functional protein; in UMD-LSDB database 15X with biological significance and a classification of class 5; in BIC Database 1X with clinical importance, class 5; and in ARUP Laboratories as definitely pathogenic. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, and the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.4391del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1464 and leads to a premature stop codon at position 1465. 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 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	RCV000031170	SCV004243989	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing