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rs8176234

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_007294.4(BRCA1):c.4987-68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,221,538 control chromosomes in the GnomAD database, including 72,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.32 ( 7830 hom., cov: 28)
Exomes 𝑓: 0.34 ( 64661 hom. )

Consequence

BRCA1
NM_007294.4 intron

Scores

2

Clinical Significance

Benign reviewed by expert panel B:10O:1

Conservation

PhyloP100: -2.25
Variant links:
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=-0.91).
BP6
Variant 17-43067763-T-C is Benign according to our data. Variant chr17-43067763-T-C is described in ClinVar as [Benign]. Clinvar id is 125746.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43067763-T-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.4987-68A>G intron_variant ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.4987-68A>G intron_variant 1 NM_007294.4 P4P38398-1

Frequencies

GnomAD3 genomes
AF:
0.316
AC:
47653
AN:
151000
Hom.:
7826
Cov.:
28
show subpopulations
Gnomad AFR
AF:
0.234
Gnomad AMI
AF:
0.284
Gnomad AMR
AF:
0.326
Gnomad ASJ
AF:
0.362
Gnomad EAS
AF:
0.369
Gnomad SAS
AF:
0.489
Gnomad FIN
AF:
0.398
Gnomad MID
AF:
0.354
Gnomad NFE
AF:
0.331
Gnomad OTH
AF:
0.333
GnomAD4 exome
AF:
0.342
AC:
365744
AN:
1070422
Hom.:
64661
AF XY:
0.348
AC XY:
191143
AN XY:
549356
show subpopulations
Gnomad4 AFR exome
AF:
0.232
Gnomad4 AMR exome
AF:
0.321
Gnomad4 ASJ exome
AF:
0.368
Gnomad4 EAS exome
AF:
0.353
Gnomad4 SAS exome
AF:
0.497
Gnomad4 FIN exome
AF:
0.396
Gnomad4 NFE exome
AF:
0.326
Gnomad4 OTH exome
AF:
0.340
GnomAD4 genome
AF:
0.316
AC:
47682
AN:
151116
Hom.:
7830
Cov.:
28
AF XY:
0.321
AC XY:
23667
AN XY:
73714
show subpopulations
Gnomad4 AFR
AF:
0.234
Gnomad4 AMR
AF:
0.327
Gnomad4 ASJ
AF:
0.362
Gnomad4 EAS
AF:
0.369
Gnomad4 SAS
AF:
0.488
Gnomad4 FIN
AF:
0.398
Gnomad4 NFE
AF:
0.331
Gnomad4 OTH
AF:
0.337
Alfa
AF:
0.317
Hom.:
971
Bravo
AF:
0.303
Asia WGS
AF:
0.416
AC:
1445
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:10Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:4Other:1
Benign, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Jan 12, 2015Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.3322 (Asian), 0.2175 (African), 0.3615 (European), derived from 1000 genomes (2012-04-30). -
not provided, no classification providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)-- -
Benign, criteria provided, single submitterclinical testingGreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited-- -
Benign, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)May 29, 2002- -
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 09, 2014- -
not specified Benign:3
Benign, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 11, 2014- -
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateApr 19, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.91
Cadd
Benign
0.55
Dann
Benign
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs8176234; hg19: chr17-41219780; COSMIC: COSV58794203; API