Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_007294.4(BRCA1):c.5467+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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 Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 17-43047635-C-T is Benign according to our data. Variant chr17-43047635-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91651.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, not_provided=1}.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:1Other:1
Uncertain significance, no assertion criteria provided
clinical testing
BRCAlab, Lund University
Mar 02, 2020
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Benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Apr 10, 2013
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Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
May 29, 2002
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not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
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not provided Uncertain:2
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Nov 29, 2013
This variant is denoted BRCA1 IVS22+8G>A or c.5467+8G>A and consists of a G>A nucleotide substitution at the +8 position of intron 22 of the BRCA1 gene. Multiple in silico prediction programs predict this variant to create a cryptic splice site that is used instead of the nearby natural donor site. The splicing defect would add 5 bases to the protein and might lead to a change the reading frame; however, it is near to the end of the protein so the clinical significance is unclear. This variant has not, to our knowledge, been published in the literature as pathogenic or benign and is listed twice in BIC as having unknown significance. BRCA1 c.5467+8G>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The intronic base is poorly conserved throughout evolution. Based on the currently available information, we cannot assess whether BRCA1 c.5467+8G>A is a pathogenic variant or a benign polymorphism. -
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Oct 16, 2023
The BRCA1 c.5467+8G>A variant has been reported in individuals affected with breast cancer in the published literature (PMID: 25682074 (2015), 16267036 (2005)). This variant has also been reported to no deleterious effect of this variant on homology directed repair (HDR) activity (PMID: 30209399 (2018)). The frequency of this variant in the general population, 0.000085 (11/129188 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on BRCA1 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites (Alamut Visual (http://www.interactive-biosoftware.com/)). Based on the available information, we are unable to determine the clinical significance of this variant. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Oct 01, 2021
Variant summary: BRCA1 c.5467+8G>A alters a 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 creates a cryptic 5' donor site. Two predict the variant strengthens a cryptic 5' donor site. The variant allele was found at a frequency of 8e-06 in 251484 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5467+8G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (example, Judkins_2005, and Wong_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant on homology directed repair (HDR) activity (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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two of these laboratories have classified the variant as likely benign and one laboratory have classified it as variant of unknown significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Sep 26, 2016
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Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter