Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5332+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,461,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as 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 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43051062-C-G is Pathogenic according to our data. Variant chr17-43051062-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 55528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43051062-C-G is described in Lovd as [Pathogenic]. Variant chr17-43051062-C-G is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Nov 16, 2023
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not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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Pathogenic, criteria provided, single submitter
clinical testing
Counsyl
Nov 15, 2017
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not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Revvity Omics, Revvity
Jul 24, 2020
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Nov 03, 2015
This variant is denoted BRCA1 c.5332+1G>C or IVS20+1G>C and consists of a G>C nucleotide substitution at the +1 position of intron 20 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as BRCA1 5451+1G>C. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported as a recurrent pathogenic variant in the Chinese population (Pan 2011). Based on the current evidence, we consider this variant to be pathogenic. -
The c.5332+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 19 of the BRCA1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This variant was observed in cohorts of patients with breast cancer (Deng M et al. Int J Cancer, 2019 Sep;145:1517-1528) and ovarian cancer (Carter NJ et al. Gynecol Oncol, 2018 Dec;151:481-488). Additionally, 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 Oct;562:217-222). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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; however, direct evidence is insufficient at this time (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Oct 18, 2021
This variant causes a G to C nucleotide substitution at the +1 position of intron 20 of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. A different mutation at this position, c.5332+1G>A, has been shown to cause the out-of-frame skipping of exon 20, resulting in a premature truncation and expected absent or non-functional protein product (PMID: 23451180, 24667779). A functional study has reported that this variant impacts BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in at least eight individuals affected with breast or ovarian cancer and has been described as a recurrent mutation in the Chinese population (PMID: 16835750, 20960228, 21901790, 30702160; Color internal data) 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Feb 19, 2022
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.5332+1G nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 11084537, 19629752, 23451180, 24667779). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 55528). This variant is also known as 5451+1G>C. Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 16324400, 16456781, 20960228). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 20 of the BRCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). -