Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5406+5G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,156 control chromosomes in the GnomAD database, with no homozygous occurrence. 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]
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43049116-C-A is Pathogenic according to our data. Variant chr17-43049116-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37667.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43049116-C-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3Uncertain:1Other:1
Pathogenic, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Jun 20, 2011
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not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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Likely pathogenic, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Oct 02, 2023
This variant causes a G to T nucleotide substitution at the +5 position of intron 21 of the BRCA1 gene, altering a conserved G nucleotide at this position. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. A different substitution c.5406+5G>C has been shown to cause the out-of-frame skipping of exon 21 that is expected to result in an absent functional protein (PMID: 22505045). A functional study has reported that this variant, c.5406+5G>T, impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in four individuals affected with breast cancer (PMID: 12491487, 26681312, 31300551, 36900375). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Feb 23, 2024
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Uncertain significance, flagged submission
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
May 29, 2002
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not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Apr 04, 2016
This variant is denoted BRCA1 IVS21+5G>T or c.5406+5G>T and consists of a G>T nucleotide substitution at the +5 position of intron 21 of the BRCA1 gene. Multiple in silico models predict this variant to result in either a decrease or complete loss of the natural splice donor site, likely leading to abnormal gene splicing. This variant, also known as IVS22+5G>T or c.5525+5G>T using alternate nomenclature, has been reported in at least one woman with a history of breast cancer (Olopade 2003). While functional studies have not been performed on this variant, an RT-PCR study of a different variant at the same nucleotide position, BRCA1 c.5406+5G>A, demonstrated exon skipping leading a frameshift and premature termination (Petrij-Bosch 1997). BRCA1 c.5406+5G>T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The guanine (G) nucleotide that is altered is conserved across species. We consider this variant to be likely pathogenic. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Nov 22, 2019
Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site. Nucleotide conservation is uninformative. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jun 27, 2024
Variant summary: BRCA1 c.5406+5G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251356 control chromosomes. c.5406+5G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Susswein_2016, Fostira_2020). These data indicate that the variant may be associated with disease. At least one functional study reports experimental evidence evaluating an impact on protein function and showed this variant as non functional on homology directed repair (HDR) activity assay (e.g. Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The following publications have been ascertained in the context of this evaluation (PMID: 30209399, 31300551, 22505045, 26681312). ClinVar contains an entry for this variant (Variation ID: 37667). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Dec 27, 2023
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. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 12491487, 26681312). This variant is also known as IVS22+5G>T. ClinVar contains an entry for this variant (Variation ID: 37667). 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: 9354803, 22505045). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. -
The c.5406+5G>T intronic pathogenic mutation results from a G to T substitution 5 nucleotides after coding exon 20 in the BRCA1 gene. This alteration, designated as IVS22+5G>T, was identified in an African American woman with breast cancer (Olopade OI et al. Cancer 2003 Jan;97:236-45). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). One 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(7726):217-222). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -