Submissions for variant NM_007294.4(BRCA1):c.668dup (p.Ala224fs)

dbSNP: rs80357537

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000112757	SCV000326375	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV001052544	SCV001216757	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-02-28	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with high risk of breast and ovarian cancers (PMID: 29446198). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 125900). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala224Glyfs*4) in the BRCA1 gene. Loss-of-function variants in BRCA1 are expected to be pathogenic (PMID: 20104584). However, an in-frame BRCA1 isoform lacking exons 8 and 9 (also known as exons 9 and 10) is highly expressed in blood from unaffected individuals and in normal breast tissue; this isoform may retain protein function and could functionally rescue loss-of-function variants within exons 8-9 (PMID: 24569164).
Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	RCV000112757	SCV001519667	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267850	SCV002551045	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362741	SCV002665356	uncertain significance	Hereditary cancer-predisposing syndrome	2020-05-29	criteria provided, single submitter	clinical testing	The c.668dupA variant, located in coding exon 8 of the BRCA1 gene, results from a duplication of A at nucleotide position 668, causing a translational frameshift with a predicted alternate stop codon (p.A224Gfs*4). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, this variant occurs in an exon that is absent in biologically relevant transcripts (Colombo M et al. Hum. Mol. Genet. 2014 Jul;23:3666-80). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV002362741	SCV004361101	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-11	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotides in exon 9 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in the absence of full-length protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncation variants in the vicinity of exons 8 and 9 have been reported in three individuals affected with high-risk breast cancer and/or ovarian cancer (PMID: 12203997, 12815604, 15642173, 33649982) and in a suspected hereditary breast and ovarian cancer family (PMID: 8764110). In one study, an exon 9 frameshift variant (c.594_597del) has been observed in compound heterozygosity with a known pathogenic missense variant, in an individual diagnosed with Fanconi anemia (PMID: 25472942). This truncation variant was inherited from the mother, who was personally affected with ovarian cancer at age 50 with a positive family history of disease. This presentation suggests that the exon 9 variant contributed to the development of disease. However, two splicing variants c.591C>T and c.594-2A>C that have been demonstrated to cause a premature translation stop signal and have been reported in individuals affected with breast and ovarian cancer, as well as in healthy unaffected individuals (PMID: 16211554, 19892845, 25639900, 27008870). The case-control, health history, tumor pathology and segregation data for the c.594-2A>C variant either indicate that this variant is not pathogenic or that pathogenicity is inconclusive (PMID: 25639900, 27008870). In these carriers, there is a relative increase in the skipping of exons 8 and 9 by pre-mRNA splicing that is expected to cause a small in-frame deletion of 41 amino acids from the reference protein (1884 amino acids) (PMID: 19892845, 27008870). An interpretation of these findings is that a BRCA1 mRNA isoform lacking exons 8 and 9 is normally produced and is functional. This alternate mRNA isoform is expected to be refractory to frameshift, nonsense and splicing defective variants found in exons 8 and 9 (PMID: 27008870). RNA studies have confirmed the appearance of the skipping of exons 8 and 9 in the majority of individuals tested, however, the degree of expression also appears to be highly variable in individuals (PMID: 24569164, 27008870, 28905878, 32133419). Taken together, the available evidence suggests that the expected deleterious effects of this c.668dup variant and other truncation variants occurring in exons 8 and 9 could be ameliorated by the expression of the mRNA isoform lacking exons 8 and 9 that retains normal BRCA1 function. Because of the uncertain clinical consequences of this variant, it is classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112757	SCV000145648	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	1999-04-06	no assertion criteria provided	clinical testing