rs80358006
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_007294.4(BRCA1):c.81-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000661 in 1,610,512 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00068 ( 2 hom. )
Consequence
BRCA1
NM_007294.4 intron
NM_007294.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.311
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 -16 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.92).
BP6
Variant 17-43115793-G-A is Benign according to our data. Variant chr17-43115793-G-A is described in ClinVar as [Benign]. Clinvar id is 37702.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43115793-G-A is described in Lovd as [Benign]. Variant chr17-43115793-G-A is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.81-14C>T | intron_variant | ENST00000357654.9 | NP_009225.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.81-14C>T | intron_variant | 1 | NM_007294.4 | ENSP00000350283.3 |
Frequencies
GnomAD3 genomes AF: 0.000441 AC: 67AN: 152072Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000397 AC: 98AN: 246832Hom.: 0 AF XY: 0.000360 AC XY: 48AN XY: 133498
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GnomAD4 exome AF: 0.000684 AC: 997AN: 1458440Hom.: 2 Cov.: 30 AF XY: 0.000663 AC XY: 481AN XY: 725432
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GnomAD4 genome AF: 0.000441 AC: 67AN: 152072Hom.: 0 Cov.: 32 AF XY: 0.000431 AC XY: 32AN XY: 74276
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:23Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:7Other:1
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Benign, criteria provided, single submitter | literature only | Counsyl | Apr 18, 2014 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Benign, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
Benign, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Feb 23, 2006 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Benign, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Jun 18, 2019 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 1.76E-08 - |
not specified Benign:9
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 22, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Benign, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 25, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The c.81-14C>T was reported in the EPS project in 8 of 8600 (0.0009) in a European cohort and 1 of 4406 African American chromosomes, increasing the likelihood this is rare variant of unlikely clinical significance. Claes et al (2003) demonstrated by RT-PCR that there was no aberrant splicing increasing the likelihood this variant does not have clinical significance. dbSNPID rs80358006. This variant was identified in the UMD database 36x and it co-occurred with a second pathogenic variant 3 times. Judkins (2005) also report this variant as co-occurring with a second pathogenic variant, increasing the likelihood this variant does not have clinical significant. Myriad genetics classifies this variant as a polymorphsim (Personal communication). In summary, based on the above information, this variant is classified as benign. - |
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 01, 2017 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 20, 2021 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 04, 2015 | - - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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