Submissions for variant NM_007294.4(BRCA1):c.3967del (p.Gln1323fs)

dbSNP: rs397509122

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)	RCV000257504	SCV000323691	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.
Ambry Genetics	RCV000220986	SCV000275675	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	The c.3967delC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 3967, causing a translational frameshift with a predicted alternate stop codon (p.Q1323Kfs*2). This alteration was reported in one German breast and ovarian cancer family (Meyer P et al. Hum. Mutat. 2003 Sep; 22(3):259). 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000257504	SCV000325801	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000657205	SCV000778931	pathogenic	not provided	2018-08-16	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in BRCA1 is denoted c.3967delC at the cDNA level and p.Gln1323LysfsX2 (Q1323KfsX2) at the protein level. The normal sequence, with the base that is deleted in brackets, is CAAA[delC]AAAT. The deletion causes a frameshift which changes a Glutamine to a Lysine at codon 1323, 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. Also reported as BRCA1 c.4086delC using alternate nomenclature, this variant has been observed in at least one individual with a family history of breast and ovarian cancer (Meyer 2003). We consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657205	SCV000887679	pathogenic	not provided	2017-11-03	criteria provided, single submitter	clinical testing
Invitae	RCV003529965	SCV004296814	pathogenic	Hereditary breast ovarian cancer syndrome	2023-08-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1323Lysfs*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 BRCA1-related conditions (PMID: 12938098, 28888541). ClinVar contains an entry for this variant (Variation ID: 55063). For these reasons, this variant has been classified as Pathogenic.