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rs144848

Variant summary

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

The NM_000059.4(BRCA2):c.1114A>C(p.Asn372His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,613,510 control chromosomes in the GnomAD database, including 63,594 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. N372D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.24 ( 4773 hom., cov: 32)
Exomes 𝑓: 0.28 ( 58821 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

15

Clinical Significance

Benign reviewed by expert panel U:2B:35O:1

Conservation

PhyloP100: 0.320
Variant links:
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [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 chr13-32332592-AA-C is described in ClinVar as [Pathogenic]. Clinvar id is 545846.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.005027443).
BP6
Variant 13-32332592-A-C is Benign according to our data. Variant chr13-32332592-A-C is described in ClinVar as [Benign]. Clinvar id is 9329.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332592-A-C is described in Lovd as [Likely_benign]. Variant chr13-32332592-A-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.1114A>C p.Asn372His missense_variant 10/27 ENST00000380152.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.1114A>C p.Asn372His missense_variant 10/275 NM_000059.4 A2

Frequencies

GnomAD3 genomes
AF:
0.238
AC:
36156
AN:
151966
Hom.:
4768
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.125
Gnomad AMI
AF:
0.295
Gnomad AMR
AF:
0.304
Gnomad ASJ
AF:
0.360
Gnomad EAS
AF:
0.258
Gnomad SAS
AF:
0.356
Gnomad FIN
AF:
0.221
Gnomad MID
AF:
0.261
Gnomad NFE
AF:
0.276
Gnomad OTH
AF:
0.261
GnomAD3 exomes
AF:
0.280
AC:
69869
AN:
249852
Hom.:
10214
AF XY:
0.285
AC XY:
38560
AN XY:
135500
show subpopulations
Gnomad AFR exome
AF:
0.125
Gnomad AMR exome
AF:
0.304
Gnomad ASJ exome
AF:
0.356
Gnomad EAS exome
AF:
0.267
Gnomad SAS exome
AF:
0.352
Gnomad FIN exome
AF:
0.230
Gnomad NFE exome
AF:
0.279
Gnomad OTH exome
AF:
0.282
GnomAD4 exome
AF:
0.281
AC:
409992
AN:
1461426
Hom.:
58821
Cov.:
37
AF XY:
0.283
AC XY:
205796
AN XY:
726994
show subpopulations
Gnomad4 AFR exome
AF:
0.125
Gnomad4 AMR exome
AF:
0.302
Gnomad4 ASJ exome
AF:
0.353
Gnomad4 EAS exome
AF:
0.236
Gnomad4 SAS exome
AF:
0.349
Gnomad4 FIN exome
AF:
0.232
Gnomad4 NFE exome
AF:
0.281
Gnomad4 OTH exome
AF:
0.276
GnomAD4 genome
AF:
0.238
AC:
36183
AN:
152084
Hom.:
4773
Cov.:
32
AF XY:
0.239
AC XY:
17733
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.125
Gnomad4 AMR
AF:
0.304
Gnomad4 ASJ
AF:
0.360
Gnomad4 EAS
AF:
0.258
Gnomad4 SAS
AF:
0.358
Gnomad4 FIN
AF:
0.221
Gnomad4 NFE
AF:
0.276
Gnomad4 OTH
AF:
0.267
Alfa
AF:
0.278
Hom.:
14900
Bravo
AF:
0.238
TwinsUK
AF:
0.282
AC:
1046
ALSPAC
AF:
0.284
AC:
1096
ESP6500AA
AF:
0.129
AC:
558
ESP6500EA
AF:
0.286
AC:
2449
ExAC
AF:
0.277
AC:
33603
Asia WGS
AF:
0.339
AC:
1177
AN:
3478
EpiCase
AF:
0.278
EpiControl
AF:
0.281

ClinVar

Significance: Benign
Submissions summary: Uncertain:2Benign:35Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:12
Benign, criteria provided, single submitterliterature onlyCounsylJan 02, 2014High frequency in a 1kG or ESP population: 28.6 %. -
Benign, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMay 03, 2020- -
Uncertain significance, no assertion criteria providedliterature onlyOMIMFeb 01, 2014- -
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 0.2552 (Asian), 0.09756 (African), 0.2876 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 09, 2014- -
Benign, criteria provided, single submitterclinical testingGreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingMichigan Medical Genetics Laboratories, University of MichiganNov 03, 2014- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterSep 21, 2015- -
Benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
not specified Benign:8Other:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 23, 2015- -
Benign, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Benign, criteria provided, single submitterclinical testingGeneKor MSANov 01, 2017- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 23, 2016p.Asn372His in exon 10 of BRCA2: This variant is not expected to have clinical s ignificance because it has been identified in 35.58% (5867/16490) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs144848). -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingCancer Genetics and Genomics Laboratory, British Columbia Cancer AgencyApr 18, 2017- -
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-- -
not provided Benign:4
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 32846166, 25348552, 21476145, 24289560, 32356124, 31477031, 29988080, 21990134, 24728327, 26306726, 27153395, 11062481, 19253839, 18288416, 22044372, 24323938, 23249957, 14555511, 15695382, 21702907, 17767707, 21952622, 20352487, 20135345, 22703879) -
Benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicNov 28, 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 breast ovarian cancer syndrome Benign:4
Benign, criteria provided, single submitterresearchGenetics Program, Instituto Nacional de CancerNov 01, 2021- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 23, 2014- -
Benign, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateApr 19, 2022- -
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 04, 2014- -
Benign, criteria provided, single submittercurationSema4, Sema4Jan 17, 2020- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 07, 2019This 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. -
Breast ductal adenocarcinoma Uncertain:1
Uncertain significance, no assertion criteria providedresearchNext Generation Diagnostics, Novartis Institutes for BioMedical Research, Inc.Jul 20, 2015- -
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Benign:1
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsApr 29, 2022- -
Fanconi anemia complementation group D1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Familial cancer of breast Benign:1
Benign, criteria provided, single submitterclinical testingBaylor GeneticsFeb 23, 2017- -
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 18, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.71
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
15
DANN
Benign
0.93
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.77
FATHMM_MKL
Benign
0.087
N
MetaRNN
Benign
0.0050
T;T
MetaSVM
Benign
-0.95
T
MutationTaster
Benign
1.0
P;P
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.60
N;N
REVEL
Benign
0.041
Sift
Benign
0.14
T;T
Sift4G
Benign
0.34
T;T
Vest4
0.081
MPC
0.021
ClinPred
0.0012
T
GERP RS
0.40
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.054

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs144848; hg19: chr13-32906729; COSMIC: COSV66448817; API