Submissions for variant NM_007294.4(BRCA1):c.4358-2del

dbSNP: rs1353755235

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001043206	SCV001206926	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-03-20	criteria provided, single submitter	clinical testing	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. Studies have shown this variant is associated with deletion of 1 amino acid (p.Ala1453del) in exon 13, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 24569164; Invitae). ClinVar contains an entry for this variant (Variation ID: 841062). 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 falls in intron 12 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein.
Color Diagnostics, LLC DBA Color Health	RCV001192311	SCV001360341	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-24	criteria provided, single submitter	clinical testing	This variant causes the deletion of a single A nucleotide within three consecutive A nucleotides located between c.4358-4 and c.4358-2 in intron 12 of the BRCA1 gene. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001192311	SCV002627939	uncertain significance	Hereditary cancer-predisposing syndrome	2015-10-22	criteria provided, single submitter	clinical testing	The c.4358-2delA intronic variant, located in intron 11 of the BRCA1 gene, results from a deletion of one nucleotide within intron 11 of the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This splice site has a known alternate splice site which results in the deletion of a single amino acid from coding exon 12, or exon 14 in the literature (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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321788	SCV004026764	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003321788	SCV004122404	uncertain significance	not specified	2023-10-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4358-2delA is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250800 control chromosomes. To our knowledge, no occurrence of c.4358-2delA in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.