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rs11571833

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBS1BS2

The NM_000059.4(BRCA2):c.9976A>T(p.Lys3326Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 1,614,156 control chromosomes in the GnomAD database, including 72 homozygotes. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. K3326K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0060 ( 3 hom., cov: 32)
Exomes 𝑓: 0.0081 ( 69 hom. )

Consequence

BRCA2
NM_000059.4 stop_gained

Scores

1
2
4

Clinical Significance

Benign reviewed by expert panel U:1B:45O:2

Conservation

PhyloP100: 0.723
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 -14 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0274 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
BP6
Variant 13-32398489-A-T is Benign according to our data. Variant chr13-32398489-A-T is described in ClinVar as [Benign]. Clinvar id is 38266.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32398489-A-T is described in Lovd as [Benign]. Variant chr13-32398489-A-T is described in Lovd as [Likely_benign]. Variant chr13-32398489-A-T is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.006 (914/152362) while in subpopulation NFE AF= 0.0085 (578/68036). AF 95% confidence interval is 0.00792. There are 3 homozygotes in gnomad4. There are 436 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.9976A>T p.Lys3326Ter stop_gained 27/27 ENST00000380152.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.9976A>T p.Lys3326Ter stop_gained 27/275 NM_000059.4 A2

Frequencies

GnomAD3 genomes
AF:
0.00601
AC:
915
AN:
152244
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00116
Gnomad AMI
AF:
0.0352
Gnomad AMR
AF:
0.00510
Gnomad ASJ
AF:
0.00547
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00683
Gnomad FIN
AF:
0.0104
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00849
Gnomad OTH
AF:
0.00621
GnomAD3 exomes
AF:
0.00660
AC:
1654
AN:
250748
Hom.:
14
AF XY:
0.00683
AC XY:
927
AN XY:
135670
show subpopulations
Gnomad AFR exome
AF:
0.00118
Gnomad AMR exome
AF:
0.00264
Gnomad ASJ exome
AF:
0.00397
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00693
Gnomad FIN exome
AF:
0.0109
Gnomad NFE exome
AF:
0.00895
Gnomad OTH exome
AF:
0.00688
GnomAD4 exome
AF:
0.00812
AC:
11863
AN:
1461794
Hom.:
69
Cov.:
31
AF XY:
0.00826
AC XY:
6006
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00120
Gnomad4 AMR exome
AF:
0.00266
Gnomad4 ASJ exome
AF:
0.00448
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00650
Gnomad4 FIN exome
AF:
0.00985
Gnomad4 NFE exome
AF:
0.00901
Gnomad4 OTH exome
AF:
0.00725
GnomAD4 genome
AF:
0.00600
AC:
914
AN:
152362
Hom.:
3
Cov.:
32
AF XY:
0.00585
AC XY:
436
AN XY:
74506
show subpopulations
Gnomad4 AFR
AF:
0.00115
Gnomad4 AMR
AF:
0.00510
Gnomad4 ASJ
AF:
0.00547
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00683
Gnomad4 FIN
AF:
0.0104
Gnomad4 NFE
AF:
0.00850
Gnomad4 OTH
AF:
0.00615
Alfa
AF:
0.00705
Hom.:
2
Bravo
AF:
0.00539
TwinsUK
AF:
0.0113
AC:
42
ALSPAC
AF:
0.00934
AC:
36
ESP6500AA
AF:
0.00272
AC:
12
ESP6500EA
AF:
0.00837
AC:
72
ExAC
AF:
0.00701
AC:
851
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.00862
EpiControl
AF:
0.00960

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:45Other:2
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:15Other:1
Benign, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)May 01, 2012- -
not provided, no classification providedliterature onlyGeneReviews-- -
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA2)May 29, 2002- -
Benign, criteria provided, single submitterliterature onlyCounsylJan 02, 2014- -
Benign, criteria provided, single submitterclinical testingGenetics and Molecular Pathology, SA PathologyJun 02, 2022The BRCA2 c.9976A>T variant is classified as Benign (BS2) -
Benign, criteria provided, single submitterclinical testingMichigan Medical Genetics Laboratories, University of MichiganNov 03, 2014- -
Likely benign, no assertion criteria providedliterature onlyPathway GenomicsJul 24, 2014- -
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Benign, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterOct 06, 2021- -
Benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterSep 21, 2015- -
Benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsFeb 22, 2016- -
Benign, reviewed by expert panelcurationClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGenApr 23, 2024The c.9976A>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Lysine at amino acid 3326 (p.Lys3326Ter). The highest non-cancer, non-founder population filter allele frequency in gnomAD v2.1 (exomes only, non-cancer subset, read depth >=20) or gnomAD v3.1 (non-cancer subset, read depth >=20) is 0.00813 in the European (non-Finnish) population, which is above the ENIGMA BRCA1/2 VCEP threshold (>0.001) for BA1 (BA1 met). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 29988080) (BS3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3.09E-263 (based on Cosegregation LR=0.001; Pathology LR=1.864E-35; Co-occurrence LR=0.0001; Case-Control LR=1.66E-221), below the threshold for Very strong benign evidence (LR <0.00285) (BP5_Very strong met; PMID: 18451181, Internal lab contributor). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BA1, BS3, BP5_Very strong). -
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 09, 2014- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not specified Benign:10Other:1
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMay 11, 2020- -
Benign, criteria provided, single submitterclinical testingGeneKor MSANov 01, 2017- -
Benign, criteria provided, single submitterclinical testingCancer Genetics and Genomics Laboratory, British Columbia Cancer AgencyApr 18, 2017- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingDepartment of Pathology and Molecular Medicine, Queen's UniversityApr 20, 2017- -
Benign, no assertion criteria providedclinical testingClinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute-- -
Benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 13, 2015- -
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, no assertion criteria providedresearchResearch Molecular Genetics Laboratory, Women's College Hospital, University of TorontoJan 31, 2014- -
not provided Benign:8
Likely benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 02, 2017- -
Benign, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsDec 27, 2016- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 22, 2023- -
Benign, no assertion criteria providedresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 13, 2012- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024BRCA2: BS2 -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 12, 2016Variant summary: The BRCA2 c.9976A>T (p.Lys3326X) variant results in a termination codon at the penultimate exon, predicted to cause a truncation of the last 93 amino acids. This variant is not expected to affect any known domain (InterPro) and no truncations downstream of this position have been reported to be pathogenic in literature and databases. This variant was found in 2327/296226 control chromosomes (including 8 homozygotes) at a frequency of 0.0078555, which is approximately 10 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this variant is likely a benign polymorphism. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as benign (14)/likely benign (1). Available family, co-occurrence and functional data also show that it is not a disease causing variant. Despite these, this variant is found at considerably high frequency, especially in patients with breast and/or ovarian cancer, raising a possibilty that it may be a risk variant. Using weighted logistic regression, Meeks et al 2016 analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Other adjustments in the study were adjustment for attained age, consortium study site, and principal components of population structure. From the study, weighted ORs for invasive breast cancer and ovarian cancers were 1.28 (confidence interval 1.17-1.4; P-value=3.84x10e-3) and 1.26 (confidence interval 1.1-1.43; P-value=3.84x10e-3), respectively. The authors conclude that this study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Hence this variant is a risk allele which attributes a significant but a low risk in development of breast or ovarian cancer. In addition, other genetic/lifestyle/environmental factors may also be playing a part in elevation of risk. Taken together, this variant is classified as Benign for HBOC. -
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:4
Uncertain significance, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateApr 19, 2022- -
Benign, criteria provided, single submitterresearchGenetics Program, Instituto Nacional de CancerNov 01, 2021- -
Benign, criteria provided, single submitterclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaJul 09, 2015- -
Benign, criteria provided, single submitterresearchCSER _CC_NCGL, University of WashingtonMar 11, 2015- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Hereditary cancer-predisposing syndrome Benign:3
Benign, no assertion criteria providedclinical testingTrue Health DiagnosticsFeb 20, 2018- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 19, 2014This 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. -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 19, 2014- -
Breast and/or ovarian cancer Benign:2
Likely benign, no assertion criteria providedclinical testingFoulkes Cancer Genetics LDI, Lady Davis Institute for Medical ResearchAug 02, 2013- -
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioDec 19, 2017- -
Malignant tumor of breast Benign:2
Likely benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The BRCA2 p.Lys3326X variant was identified in 1577 of 158144 proband chromosomes (frequency: 0.010) from various ethnicities in multinational cohorts of individuals or families with breast and ovarian cancer and was present in 1414 of 167882 control chromosomes (frequency: 0.008) from healthy individuals (Hadjisavvas 2004 15172753, Wagner 1999 9971877, Borg 2010 20104584, Claes 2003 12759930, Meeks 2016 26586665). The variant was also identified in dbSNP (ID: rs11571833) as “With other allele”, ClinVar (Benign by ENIGMA, DVD CHOP, Michigan Medical Genetics, CSER_CC_NCGL University of Washington Medical Center, Colour Genomics, Prevention Genetics, Invitae, Counsyl, Ambry Genetics, Laboatroy Corporation of America Study Description, Children's Mercy Hospital, Fulgent, Cancer Genetic and Genomic Laboratory BC, EGL Genetic Diagnostics, Queen's University Department of Pathology, ARUP, Women's College Hospital, BIC, SCRP, and Biesecker Lab, as likely benign by Illumina, CHEO, and Pathway Genomics and as pathogenic by GeneReviews.), in ClinVitae (7x as Benign in 4 entries including 3 from ClinVar and 1 from EmyClass, as Conflicting interpretations of pathogenicity from Invitae and ClinVar, and as a polymorphism by kConFab), COSMIC (1x observed in alveolar rhabdomyosarcoma, as neutral), LOVD 3.0 (65x as does not affect function, affect unknown or unclassified), UMD-LSDB (114 entries, classified as neutral and reported as co-occuring with pathogenic BRCA2 and BRCA1 variants), BIC Database (301 entries, classification pending), and ARUP Laboratories (classified as not pathogenic or of no clinical significance). The variant was not identified in MutDB, or the Zhejiang Colon Cancer Database. The variant was also identified by our laboratory in 111 individuals with breast, ovarian, pancreatic, or brain cancer. The variant was identified in control databases in 1782 of 276718 chromosomes (13 homozygous) at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 35 of 23984 chromosomes (freq: 0.001), Other in 48 of 6448 chromosomes (freq: 0.007), Latino in 95 of 34342 chromosomes (freq: 0.003), European Non-Finnish in 1089 of 126410 chromosomes (freq: 0.009), Ashkenazi Jewish in 41 of 10146 chromosomes (freq: 0.004), European Finnish in 266 of 25780 chromosomes (freq: 0.01), and South Asian in 208 of 30764 chromosomes (freq: 0.007) while the variant was not observed in the East Asian population. The c.9976A>T variant leads to a premature stop codon in the penultimate exon of BRCA2 and is predicted to cause a truncation of the last 93 amino acids. There is conflicting evidence in the literature regarding the significance of this variant. The variant was shown to have a 1.26 fold increase in breast cancer risk (in heterozygous form) or 5.78 increase risk (in homozygous form) (95% confidence interval p=1.2x10-5) and/or is in linkage disequilibrium with higher risk variants in a study looking at SNPs selected on the basis of genome wide association studies, genotyped in 45,290 cases and 41,880 controls from 41 studies (Michailidou 2013 23535729). A more recent study of the c.9976A>T variant identified 852/41081 carriers of the variant in women with breast cancer, and 322/14514 with ovarian cancer. They determined an odds ratio of adjusted for the probability of carrying a pathogenic BRCA1/2 variant of 1.28 for the breast cancer group, 1.52 for the triple negative breast cancer group and 1.46 for the serous ovarian cancer group (Meeks 2016 26586665). A posterior probability model integrating causality models based on prior probability derived from evolutionary conservation and likelihoods of causality, indicate that this variant is not pathogenic (Lindor_2012_21990134). However, in vitro splicing assays on 31 BRCA2 variants showed this variant to be pathogenic despite not being pathogenic ba -
Benign, no assertion criteria providedresearchCenter of Medical Genetics and Primary Health CareApr 08, 2020ACMG Guidelines 2015 criteria -
Fanconi anemia complementation group D1 Benign:1
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.026
T
BayesDel_noAF
Pathogenic
0.27
Cadd
Pathogenic
34
Dann
Uncertain
0.97
Eigen
Benign
0.0040
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.044
N
MutationTaster
Benign
1.0
A;D
Vest4
0.64
GERP RS
0.16

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: rs11571833; hg19: chr13-32972626; COSMIC: COSV66337127; COSMIC: COSV66337127; API