13-32339553-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000059.4(BRCA2):​c.5198C>T​(p.Ser1733Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,607,336 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. S1733S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

1
3
12

Clinical Significance

Benign reviewed by expert panel U:4B:28

Conservation

PhyloP100: 0.540
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.011440545).
BP6
Variant 13-32339553-C-T is Benign according to our data. Variant chr13-32339553-C-T is described in ClinVar as [Benign]. Clinvar id is 37950.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339553-C-T is described in Lovd as [Benign]. Variant chr13-32339553-C-T 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
BRCA2NM_000059.4 linkuse as main transcriptc.5198C>T p.Ser1733Phe missense_variant 11/27 ENST00000380152.8 NP_000050.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.5198C>T p.Ser1733Phe missense_variant 11/275 NM_000059.4 ENSP00000369497 A2

Frequencies

GnomAD3 genomes
AF:
0.000684
AC:
104
AN:
152044
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00210
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00259
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000426
AC:
105
AN:
246462
Hom.:
0
AF XY:
0.000472
AC XY:
63
AN XY:
133420
show subpopulations
Gnomad AFR exome
AF:
0.00234
Gnomad AMR exome
AF:
0.0000888
Gnomad ASJ exome
AF:
0.00102
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00157
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000536
Gnomad OTH exome
AF:
0.000502
GnomAD4 exome
AF:
0.000236
AC:
344
AN:
1455174
Hom.:
2
Cov.:
44
AF XY:
0.000268
AC XY:
194
AN XY:
723888
show subpopulations
Gnomad4 AFR exome
AF:
0.00392
Gnomad4 AMR exome
AF:
0.0000911
Gnomad4 ASJ exome
AF:
0.00158
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00133
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.000549
GnomAD4 genome
AF:
0.000697
AC:
106
AN:
152162
Hom.:
0
Cov.:
33
AF XY:
0.000753
AC XY:
56
AN XY:
74396
show subpopulations
Gnomad4 AFR
AF:
0.00214
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00259
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000237
Hom.:
0
Bravo
AF:
0.000865
ESP6500AA
AF:
0.00296
AC:
13
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000470
AC:
57
Asia WGS
AF:
0.000289
AC:
1
AN:
3474

ClinVar

Significance: Benign
Submissions summary: Uncertain:4Benign:28
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1Benign:7
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Feb 11, 2008- -
Likely benign, criteria provided, single submitterclinical testingMichigan Medical Genetics Laboratories, University of MichiganApr 21, 2016- -
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 = 0.000000000153 -
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA2)May 29, 2002- -
Likely benign, criteria provided, single submitterliterature onlyCounsylFeb 28, 2014- -
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024- -
not provided Uncertain:2Benign:4
Uncertain significance, no assertion criteria providedresearchBiesecker Lab/Clinical Genomics Section, National Institutes of HealthJul 13, 2012- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 12, 2018- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Likely benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicMar 29, 2017- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024BRCA2: BP4 -
not specified Benign:6
Likely benign, criteria provided, single submitterclinical testingInstitute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's HospitalMay 19, 2017BS1,BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJun 02, 2017- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 20, 2018- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 13, 2017This 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, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Hereditary cancer-predisposing syndrome Benign:4
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 24, 2015- -
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 submittercurationSema4, Sema4Aug 11, 2020- -
Likely benign, criteria provided, single submitterclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Jan 16, 2018- -
Hereditary breast ovarian cancer syndrome Benign:3
Benign, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateApr 19, 2022- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024- -
Benign, no assertion criteria providedclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Sep 27, 2021- -
Fanconi anemia complementation group D1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 22, 2022- -
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioMay 01, 2023- -
BRCA2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 17, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Malignant tumor of breast Benign:1
Benign, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The p.Ser1733Phe variant has been reported in the literature in 1 of 1410 proband chromosomes (f=0.001) of young women with contralateral breast cancer, and in no chromosomes of young women with unilateral breast cancer chromosomes in this study (n=2796) (Borg 2010). In literature, it is also considered a “well-documented missense polymorphism” (Hearle 2003) with high odds in favour of neutrality (Easton 2007). This variant has been observed in the UMD (4x) database as a neutral polymorphism, and is listed in the CNPHI database with ACMG category 5. It is also listed in dbSNP (ID# rs55639415) as a single nucleotide variation with a minor allele frequency of 0.002 having been observed in 4 chromosomes (1000 Genomes). This variant has been reported in the EVS with a minor allele frequency of 0.001. This residue is conserved in mammals; however, computational analyses (PolyPhen, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, based on the above information, this variant is classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
17
DANN
Uncertain
0.98
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.61
FATHMM_MKL
Benign
0.069
N
M_CAP
Benign
0.035
D
MetaRNN
Benign
0.011
T;T
MetaSVM
Benign
-0.95
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.30
T
PROVEAN
Pathogenic
-4.5
D;D
REVEL
Benign
0.16
Sift
Uncertain
0.024
D;D
Sift4G
Uncertain
0.022
D;D
Vest4
0.51
MVP
0.85
MPC
0.029
ClinPred
0.0069
T
GERP RS
2.5
gMVP
0.23

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: rs55639415; hg19: chr13-32913690; API