Submissions for variant NM_007294.4(BRCA1):c.1374del (p.Asp458fs)

dbSNP: rs397508862

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000257244	SCV000323307	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	RCV000257244	SCV000325049	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001011250	SCV001171549	pathogenic	Hereditary cancer-predisposing syndrome	2019-08-19	criteria provided, single submitter	clinical testing	The c.1374delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1374, causing a translational frameshift with a predicted alternate stop codon (p.D458Efs*17). This mutation (also designated as 1493delC) has been identified in multiple high-risk breast/ovarian cancer families from South Africa and has been described as a common mutation in that population (Reeves MD et al. Int. J. Cancer, 2004 Jul;110:677-82; Schoeman M et al. S. Afr. Med. J., 2013 Jun;103:529-33). 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.
Invitae	RCV001071649	SCV001236962	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp458Glufs*17) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer and fallopian tube cancer (PMID: 15146556, 26915939, 29446198). This variant is also known as 1493delC. ClinVar contains an entry for this variant (Variation ID: 54224). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001071649	SCV001467969	pathogenic	Hereditary breast ovarian cancer syndrome	2020-12-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1374delC (p.Asp458GlufsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251028 control chromosomes. c.1374delC has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001071649	SCV002505006	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing