Submissions for variant NM_007294.4(BRCA1):c.4516del (p.Asp1506fs)

dbSNP: rs273900736

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)	RCV000112352	SCV000300132	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	RCV000112352	SCV000325991	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774941	SCV000909020	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-17	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 14 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 individuals affected with breast and/or ovarian cancer (PMID: 18763032, 25066507, 25948282). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504475	SCV001431911	pathogenic	Hereditary breast ovarian cancer syndrome	2020-08-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4516delG (p.Asp1506IlefsX42) 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 251352 control chromosomes. c.4516delG has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018, Kluska_2015). These data indicate that the variant is likely to be associated with disease. One clinical diagnostic laboratory, the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000504475	SCV003442378	pathogenic	Hereditary breast ovarian cancer syndrome	2022-09-15	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: 55220). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18763032, 25948282). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp1506Ilefs*42) 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).
Ambry Genetics	RCV000774941	SCV003911980	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-17	criteria provided, single submitter	clinical testing	The c.4516delG pathogenic mutation, located in coding exon 13 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 4516, causing a translational frameshift with a predicted alternate stop codon (p.D1506Ifs*42). This alteration has been observed in multiple patients with personal and/or family history of breast and/or ovarian cancer (Janavicius R et al. Breast Cancer Res Treat, 2009 Sep;117:467-9; Kluska A et al. BMC Med Genomics, 2015 May;8:19). 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001353699	SCV005196943	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112352	SCV000145112	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2007-08-27	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353699	SCV000591525	uncertain significance	not provided		no assertion criteria provided	clinical testing