rs8176258
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_007294.4(BRCA1):c.5075-53C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,533,560 control chromosomes in the GnomAD database, including 535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.019 ( 42 hom., cov: 32)
Exomes 𝑓: 0.024 ( 493 hom. )
Consequence
BRCA1
NM_007294.4 intron
NM_007294.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.152
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
?
Variant 17-43064004-G-A is Benign according to our data. Variant chr17-43064004-G-A is described in ClinVar as [Benign]. Clinvar id is 125760.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43064004-G-A is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0187 (2848/152268) while in subpopulation NFE AF= 0.0273 (1854/68008). AF 95% confidence interval is 0.0262. There are 42 homozygotes in gnomad4. There are 1387 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 42 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.5075-53C>T | intron_variant | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.5075-53C>T | intron_variant | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0187 AC: 2848AN: 152150Hom.: 42 Cov.: 32
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GnomAD4 exome AF: 0.0238 AC: 32886AN: 1381292Hom.: 493 AF XY: 0.0232 AC XY: 16024AN XY: 691340
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:11
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:4
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jan 12, 2015 | Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.03166 (European), derived from 1000 genomes (2012-04-30). - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Feb 20, 2004 | - - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 09, 2014 | - - |
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Vantari Genetics | Nov 27, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 05, 2015 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Malignant tumor of breast Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA1 c.5075-53C>T variant is not expected to have clinical significance as it occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified in 2 of 148 proband chromosomes (frequency: 0.027) from individuals or families with breast cancer and was present in 2 of 480 control chromosomes (frequency: 0.0.004) from healthy individuals (Cvok 2008, Jara 2006, Pietschmann 2005). This variant was identified in several populations at polymorphic frequencies, including: the 1000 Genomes Project (frequency: 0.015), HAPMAP-CEU (frequency: 0.034), HAP-YRI (frequency: 0.031), and the European American population of the ESP Project (frequency: 0.02). The variant was also listed in dbSNP (ID: rs8176258) “With Uncertain significance allele”, the ClinVar database, the BIC database (20X with no clinical importance and categorized as Class 1: Not pathogenic/low clinical significance), and in UMD (209X as a neutral variant). In the UMD database, the variant was identified with 12 different co-occurring pathogenic BRCA1 variants and 11 different co-occurring pathogenic BRCA2 variants, increasing the likelihood that the c.5075-53C>T variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at