Submissions for variant NM_007294.4(BRCA1):c.5407-1G>A

dbSNP: rs80358029

Total submissions: 9

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	RCV000112642	SCV000326305	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001024050	SCV001186004	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-25	criteria provided, single submitter	clinical testing	The c.5407-1G>A pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 21 of the BRCA1 gene. This alteration occurs at the 3' terminus of the BRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 29 amino acids of the protein. The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000496433	SCV001578084	pathogenic	Hereditary breast ovarian cancer syndrome	2020-03-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 30209399). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 125845). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 21 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002477263	SCV002774313	pathogenic	not provided	2021-08-12	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-acceptor site and is predicted to interfere with normal BRCA1 mRNA splicing. The variant has been identified in a large, worldwide study of BRCA1/2 mutation positive families in the published literature (PMID: 29446198 (2018)). In addition, functional studies in the published literature demonstrate that this variant is damaging to BRCA1 protein function, however further studies are needed to determine the global effect of this variant on BRCA1-related cancers (PMID: 30209399 (2018)). Based on the available information, this variant is classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112642	SCV000145498	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496433	SCV000587504	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353913	SCV000591628	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The c.5407-1G>A variant was not identified in the literature nor was it identified in NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, Fanconi Anemia Mutation Database (LOVD), COSMIC, ARUP Laboratories BRCA Mutations Database, GeneInsight COGR, or UMD. The variant was identified in dbSNP (ID: rs80358029) “With Pathogenic allele”, BIC (1X with clinical importance, pending classification), Clinvitae database (classification pathogenic), and the ClinVar database (classification pathogenic, no assertion criteria provided by BIC). The c.5407-1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Brotman Baty Institute, University of Washington	RCV000112642	SCV001242731	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
BRCAlab, Lund University	RCV000112642	SCV004243916	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing