Submissions for variant NM_007294.4(BRCA1):c.1499del (p.Asn500fs)

dbSNP: rs397508874

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000256726	SCV000323323	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-10-18	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	RCV000256726	SCV000325082	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002257392	SCV002538035	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-08-27	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514230	SCV003441971	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-27	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: 54271). This variant is also known as 1618delA. This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 21324516). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn500Ilefs*3) 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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356343	SCV001551485	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Asn500IlefsX3 variant was identified in 1 of 2684 proband chromosomes (frequency: 0.0004) from an Ontario based population of individuals or families with ovarian cancer (Zhang 2011). The variant was also identified in dbSNP (ID: rs397508874) as “With Pathogenic allele”, Clinvitae database (classification pathogenic), ARUP Laboratories BRCA Mutations Database (classification definitely pathogenic), COSMIC, the ClinVar database (classification definitely pathogenic, reviewed by an expert panel, submitters ENIGMA and CIMBA, and classification not provided by Invitae); and was not identified in GeneInsight COGR database, the BIC database, UMD, Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, 1000 Genomes Project, NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium database (August 8, 2016). The c.1499delA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 500 and leads to a premature stop codon 3 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 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.