Submissions for variant NM_007294.4(BRCA1):c.1757del (p.Pro586fs)

dbSNP: rs80357723

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)	RCV000111675	SCV000299644	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	RCV000132331	SCV000187419	pathogenic	Hereditary cancer-predisposing syndrome	2015-11-19	criteria provided, single submitter	clinical testing	The c.1757delC pathogenic mutation (also known as 1876delC), located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 1757, causing a translational frameshift with a predicted alternate stop codon. This mutation has been described in a patient with breast cancer at 37 years of age, though it was not detected in the patient's mother, who had breast cancer at 48 years of age (Hopper JL et al. Cancer Epidemiol. Biomarkers Prev. 1999 Sep; 8(9):741-7). In addition to the clinical data found in the literature, 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).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000111675	SCV000325133	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000657213	SCV000778939	pathogenic	not provided	2017-05-15	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA1 is denoted c.1757delC at the cDNA level and p.Pro586LeufsX2 (P586LfsX2) at the protein level. The normal sequence, with the base that is deleted in brackets, is GAAC[delC]TATA. The deletion causes a frameshift which changes a Proline to a Leucine at codon 586, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.1757delC, also published as 1876delC using alternate nomenclature, has been observed in at least one individual with Hereditary Breast and Ovarian Cancer (Hopper 1999, Southey 1999, Turkovic 2010). We consider this variant to be pathogenic.
Invitae	RCV001388572	SCV001589618	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Pro586Leufs*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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10498392, 28724667, 29446198, 30702160). ClinVar contains an entry for this variant (Variation ID: 54343).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111675	SCV000144173	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1998-11-30	no assertion criteria provided	clinical testing