Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5406+4A>G variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 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]
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43049117-T-C is Pathogenic according to our data. Variant chr17-43049117-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Quest Diagnostics Nichols Institute San Juan Capistrano
Sep 27, 2016
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Oct 18, 2019
Non-canonical splice site variant demonstrated to result in loss-of-function (Wappenschmidt 2012, Kraus 2017); Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing (SGE) assay measuring cell growth (Findlay 2018); Observed in individuals with ovarian cancer (Wappenschmidt 2012, Kraus 2017); Not observed in large population cohorts (Lek 2016); Also known as BRCA1 5525+4A>G; This variant is associated with the following publications: (PMID: 23239986, 30209399, 27616075) -
The c.5406+4A>G intronic pathogenic mutation results from an A to G substitution 4 nucleotides after coding exon 20 in the BRCA1 gene. Multiple studies with patient-derived RNA showed that the cDNA had skipping of coding exon 20 (also known as Exon 22) leading to a frameshift with predicted premature termination codon (Wappenschmidt B et al. PLoS ONE, 2012 Dec;7:e50800; Kraus C et al. Int. J. Cancer, 2017 Jan;140:95-102). A similar alteration, BRCA1 c.5406+5C>G was shown to have the same splice defect (Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38). Another functional study found that this nucleotide substitution is deleterious in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jan 02, 2020
This variant causes an A>G nucleotide substitution at the +4 position of intron 21 of the BRCA1 gene. Functional RNA studies have shown that this variant causes skipping of exon 22, resulting in premature truncation of the BRCA1 protein (PMID 27616075, 23239986). To our knowledge, functional studies of protein function have not been performed for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer in the literature (PMID 27616075, 23239986). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Other:1
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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Pathogenic, no assertion criteria provided
clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center
May 05, 2023
A pathogenic mutation ws detected in the BRCA1 gene. The c.5469+4A>G, also known as c.5406+4A>G in the literature, intronic variant results from an A to G substitution 4 nucleotides after coding exon 20 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; and multiple studies with patient-derived RNA showed that the cDNA had skipping of coding exon 20 (also known as Exon 22) leading to a frameshift with predicted premature termination codon (Wappenschmidt B et al. PLoS ONE, 2012 Dec;7:e50800; Kraus C et al. Int. J. Cancer, 2017 Jan;140:95-102). ClinVar has an entry for this variant with 5 submissions, all of which describe it as pathogenic or likely pathogenic. Therefore, this variant has been classified as pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Apr 23, 2022
ClinVar contains an entry for this variant (Variation ID: 55563). 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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 23239986, 27616075). This variant is also known as IVS22+4A>G. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 21 (also known as exon 22) and introduces a premature termination codon (PMID: 23239986, 27616075). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -