Submissions for variant NM_007294.4(BRCA1):c.4379del (p.Ser1460fs)

dbSNP: rs786203149

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241073	SCV000300110	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.
Ambry Genetics	RCV000166328	SCV000217114	pathogenic	Hereditary cancer-predisposing syndrome	2014-10-20	criteria provided, single submitter	clinical testing	The c.4379delG pathogenic mutation (also known as 4498delG), located in coding exon 12 of the BRCA1 gene, results from a deletion of one nucleotide at position 4379, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Invitae	RCV000702789	SCV000831658	pathogenic	Hereditary breast ovarian cancer syndrome	2022-02-20	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: 186693). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1460Ilefs*6) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000702789	SCV004241934	pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4379delG (p.Ser1460IlefsX6) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251060 control chromosomes (gnomAD). c.4379delG has been reported in the literature in at-least one individual affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Shah_2018). The following publication has been ascertained in the context of this evaluation (PMID: 29785135). Two submitters (including an expert panel ENIGMA) have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.