Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_007294.4(BRCA1):c.5152+6T>C variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.000000687 in 1,456,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-43063868-A-G is Pathogenic according to our data. Variant chr17-43063868-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 125777.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=2}.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1Uncertain:2Other:1
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Nov 25, 2004
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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
Kong lab, Department of Laboratory Medicine, National Cancer Center
Aug 01, 2020
The c.5152+6T>C variant in BRCA1 has been detected in a PT51 patient, who was diagnosed with triple-negative breast cancer (TNBC) IDC at 39 years of age. BRCA1 c.5152+6T>C mRNA transcripts were abnormal compared with their corresponding wild-type transcripts (effect on RNA splicing); this variant produced a combined exon 17 and 19 by exon 18 skipping in BRCA1 and was predicted to be an in-frame deletion (26 amino acids: 1692~1717 a.a.) of the BRCA1 C-terminal (BRCT) domain of BRCA1 (Ryu 2020; PMID: 32761968). This variant does not have frequency information in genome databases, including ExAC (http://exac.broadinstitute.org/) and gnomAD (http://gnomad.broadinstitue.org), and has not been reported in the literature. Moreover, BRCA1 c.5152+6T>C was not detected in the 393 healthy female Korean controls (Ryu 2020; PMID: 32761968). By employing a saturation-genome-editing technique based on CRISPR-mediated homology-directed repair, Findlay et al suggested that BRCA1 c.5152+6T>C is a loss-of-function variant (PMID: 30209399). Thus, BRCA1 c.5152+6T>C has been classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter
Likely pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Feb 07, 2023
This variant causes a T to C nucleotide substitution at the +6 position of intron 17 of the BRCA1 gene. Multiple splicing prediction tools indicate this variant may impair RNA splicing. RNA studies have reported that this variant causes aberrant splicing and in-frame skipping of exon 17 (exon 18 based on the BIC nomenclature) (PMID: 32123317, 32761968). The aberrant transcript is expected to result in nonfunctional protein product with p.Asp1692_Trp1718delinsGly in the BRCT1 domain of the BRCA1 protein. This variant has also been reported to result in the loss of BRCA1 protein function in a haploid cell proliferation assay (PMID: 30209399). Other nucleotide substitutions at the same position, c.5152+6T>A and c.5152+6T>G, are also reported to result in loss of BRCA1 function in the same study (PMID: 30209399). This variant has been observed in an individual with triple-negative breast cancer with family history of ovarian cancer in a second-degree relative (PMID: 32761968) and in an individual with ovarian cancer (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 Likely Pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 27, 2022
The c.5152+6T>C intronic pathogenic mutation results from a T to C substitution 6 nucleotides after coding exon 16 in the BRCA1 gene. Two functional studies have found that this nucleotide substitution is deleterious (Findlay GM et al. Nature. 2018 10;562:217-222; Wai HA et al. Genet Med. 2020 06;22:1005-1014). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. A close match alteration at the same nucleotide position, BRCA1 c.5152+6T>G, demonstrated abnormal splicing in the set of samples tested (Ambry internal data). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Jun 20, 2022
Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 125777). 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 17 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. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399, 32123317). 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. 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. -