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rs799917

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_007294.4(BRCA1):c.2612C>T(p.Pro871Leu) variant causes a missense change. The variant allele was found at a frequency of 0.376 in 1,613,362 control chromosomes in the GnomAD database, including 124,333 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P871L?) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.49 ( 21276 hom., cov: 32)
Exomes 𝑓: 0.36 ( 103057 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

18

Clinical Significance

Benign reviewed by expert panel B:36O:1

Conservation

PhyloP100: 4.25
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 -18 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43092919-G-AA is described in ClinVar as [Pathogenic]. Clinvar id is 54620.Status of the report is reviewed_by_expert_panel, 3 stars.
BP4
Computational evidence support a benign effect (MetaRNN=9.915395E-7).
BP6
Variant 17-43092919-G-A is Benign according to our data. Variant chr17-43092919-G-A is described in ClinVar as [Benign]. Clinvar id is 41812.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092919-G-A is described in Lovd as [Benign]. Variant chr17-43092919-G-A is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA1NM_007294.4 linkuse as main transcriptc.2612C>T p.Pro871Leu missense_variant 10/23 ENST00000357654.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA1ENST00000357654.9 linkuse as main transcriptc.2612C>T p.Pro871Leu missense_variant 10/231 NM_007294.4 P4P38398-1

Frequencies

GnomAD3 genomes
AF:
0.487
AC:
74015
AN:
151956
Hom.:
21221
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.810
Gnomad AMI
AF:
0.286
Gnomad AMR
AF:
0.390
Gnomad ASJ
AF:
0.364
Gnomad EAS
AF:
0.371
Gnomad SAS
AF:
0.524
Gnomad FIN
AF:
0.407
Gnomad MID
AF:
0.434
Gnomad NFE
AF:
0.341
Gnomad OTH
AF:
0.459
GnomAD3 exomes
AF:
0.404
AC:
101374
AN:
251034
Hom.:
22738
AF XY:
0.402
AC XY:
54484
AN XY:
135700
show subpopulations
Gnomad AFR exome
AF:
0.825
Gnomad AMR exome
AF:
0.348
Gnomad ASJ exome
AF:
0.377
Gnomad EAS exome
AF:
0.379
Gnomad SAS exome
AF:
0.532
Gnomad FIN exome
AF:
0.404
Gnomad NFE exome
AF:
0.334
Gnomad OTH exome
AF:
0.378
GnomAD4 exome
AF:
0.364
AC:
532630
AN:
1461288
Hom.:
103057
Cov.:
62
AF XY:
0.368
AC XY:
267321
AN XY:
726932
show subpopulations
Gnomad4 AFR exome
AF:
0.831
Gnomad4 AMR exome
AF:
0.356
Gnomad4 ASJ exome
AF:
0.371
Gnomad4 EAS exome
AF:
0.353
Gnomad4 SAS exome
AF:
0.528
Gnomad4 FIN exome
AF:
0.397
Gnomad4 NFE exome
AF:
0.335
Gnomad4 OTH exome
AF:
0.389
GnomAD4 genome
AF:
0.487
AC:
74125
AN:
152074
Hom.:
21276
Cov.:
32
AF XY:
0.488
AC XY:
36241
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.811
Gnomad4 AMR
AF:
0.390
Gnomad4 ASJ
AF:
0.364
Gnomad4 EAS
AF:
0.370
Gnomad4 SAS
AF:
0.522
Gnomad4 FIN
AF:
0.407
Gnomad4 NFE
AF:
0.341
Gnomad4 OTH
AF:
0.462
Alfa
AF:
0.355
Hom.:
25841
Bravo
AF:
0.497
TwinsUK
AF:
0.347
AC:
1288
ALSPAC
AF:
0.344
AC:
1324
ESP6500AA
AF:
0.800
AC:
3525
ESP6500EA
AF:
0.336
AC:
2889
ExAC
AF:
0.410
AC:
49775
Asia WGS
AF:
0.473
AC:
1644
AN:
3478
EpiCase
AF:
0.333
EpiControl
AF:
0.342

ClinVar

Significance: Benign
Submissions summary: Benign:36Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:14
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024- -
Benign, criteria provided, single submitterclinical testingIntelligeneCGAug 18, 2017- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, criteria provided, single submitterliterature onlyCounsylJan 02, 2014High frequency in a 1kG or ESP population: 33.6 %. -
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 09, 2014- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Benign, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Mar 22, 2011- -
Benign, criteria provided, single submitterclinical testingMichigan Medical Genetics Laboratories, University of MichiganNov 03, 2014- -
Benign, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Aug 10, 2015IARC 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 = 0.00000000000204. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.3304 (Asian), 0.1362 (African), 0.3654 (European), derived from 1000 genomes (2012-04-30). -
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)Jun 21, 1999- -
Benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterSep 21, 2015- -
not specified Benign:8Other:1
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineDec 02, 2016p.Pro871Leu in exon 10 of BRCA1: This variant is not expected to have clinical s ignificance because it has been identified in 82% (8522/10402) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs799917}). -
Benign, criteria provided, single submitterclinical testingCancer Genetics and Genomics Laboratory, British Columbia Cancer AgencyApr 18, 2017- -
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 07, 2016- -
Benign, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-#N/A -
Benign, criteria provided, single submitterclinical testingGeneKor MSANov 01, 2017- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Hereditary breast ovarian cancer syndrome Benign:4
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, criteria provided, single submitterresearchGenetics Program, Instituto Nacional de CancerNov 01, 2021- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 19, 2013- -
Benign, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateApr 19, 2022- -
not provided Benign:3
Benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicDec 07, 2016- -
Benign, no assertion criteria providedresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 13, 2012- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submittercurationSema4, Sema4Dec 11, 2019- -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 02, 2022- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 13, 2015This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Familial cancer of breast Benign:2
Benign, criteria provided, single submitterclinical testingBaylor GeneticsFeb 23, 2017- -
Benign, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMay 03, 2020- -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 06, 2022- -
Breast carcinoma Benign:1
Benign, criteria provided, single submitterclinical testingCenter for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Faculty of Medicine Ramathibodi Hospital, Mahidol UniversityApr 22, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.042
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.40
Cadd
Benign
17
Dann
Benign
0.88
DEOGEN2
Benign
0.13
T;.;.;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.67
FATHMM_MKL
Benign
0.017
N
LIST_S2
Benign
0.61
T;T;T;T
MetaRNN
Benign
9.9e-7
T;T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-3.4
N;N;.;.
MutationTaster
Benign
1.0
P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI
Benign
0.42
T
PROVEAN
Benign
5.7
N;N;N;N
REVEL
Benign
0.14
Sift
Benign
1.0
T;T;T;T
Sift4G
Benign
1.0
T;T;T;T
Polyphen
0.0
B;.;.;B
Vest4
0.31
MPC
0.082
ClinPred
0.0025
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.020
gMVP
0.084

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: rs799917; hg19: chr17-41244936; COSMIC: COSV58784386; COSMIC: COSV58784386; API