Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.5406+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-43049116-C-G is Pathogenic according to our data. Variant chr17-43049116-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:1
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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not providedPathogenic:1
Nov 06, 2018
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Not found in the total gnomAD dataset, and the data are high quality (0/282728 chr). Found in at least one symptomatic patient. Predicted to negatively affect a known splice site and shown to result in the skipping of exon 22. Nucleotide conservation is uninformative. -
The c.5406+5G>C pathogenic intronic variant results from a G to C substitution 5 nucleotides after coding exon 20 in the BRCA1 gene. This intronic variant has been reported in two unrelated individuals with triple negative breast cancer at ages 38 and 31 (Fostira F et al. Breast Cancer Res Treat. 2012 Jul;134(1):353-62). This variant has also been reported in 1 of 473 breast/ovarian cancer patients with a positive family history from a Greek cohort (Konstantopoulou I et al, Clin. Genet. 2014 Jan; 85(1):36-42). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site. This alteration was shown to result in coding exon 20 skipping (Ambry internal data; Houdayer C et al Hum. Mutat. 2012 Aug; 33(8):1228-38). Of note, this alteration is also designated as IVS22+5G>C in published literature. A similar intronic alteration, c.5406+5G>A, has also been shown to lead to coding exon 20 skipping (Petrij-Bosch A et al. Nat Genet. 1997 Nov;17(3):341-5). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Hereditary breast ovarian cancer syndromePathogenic:1
Mar 21, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.5406+5 nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12491487, 26681312, 26083025, 14985394, 9354803, 10090482). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with exon 22 skipping, which introduces a premature termination codon (PMID: 22505045). The resulting mRNA is expected to undergo nonsense-mediated decay. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 protein function (PMID: 30209399). This variant has been observed in individual(s) with breast cancer (PMID: 22434525, 24010542). This variant is also known as IVS22+5G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 55565). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 21 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. -