chr13-32379251-T-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000059.4(BRCA2):​c.8755-66T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,499,332 control chromosomes in the GnomAD database, including 205,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.52 ( 20438 hom., cov: 33)
Exomes 𝑓: 0.52 ( 184643 hom. )

Consequence

BRCA2
NM_000059.4 intron

Scores

2

Clinical Significance

Benign reviewed by expert panel B:12O:1

Conservation

PhyloP100: -1.18

Publications

95 publications found
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]
BRCA2 Gene-Disease associations (from GenCC):
  • breast-ovarian cancer, familial, susceptibility to, 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
  • Fanconi anemia complementation group D1
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
  • pancreatic cancer, susceptibility to, 2
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • sarcoma
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • hereditary breast ovarian cancer syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Fanconi anemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • medulloblastoma
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 13-32379251-T-C is Benign according to our data. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379251-T-C is described in CliVar as Benign. Clinvar id is 126190.Status of the report is reviewed_by_expert_panel, 3 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.8755-66T>C intron_variant Intron 21 of 26 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.8755-66T>C intron_variant Intron 21 of 26 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.8386-66T>C intron_variant Intron 21 of 26 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.*813-66T>C intron_variant Intron 20 of 25 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.517
AC:
78588
AN:
151904
Hom.:
20418
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.500
Gnomad AMI
AF:
0.431
Gnomad AMR
AF:
0.529
Gnomad ASJ
AF:
0.472
Gnomad EAS
AF:
0.571
Gnomad SAS
AF:
0.479
Gnomad FIN
AF:
0.573
Gnomad MID
AF:
0.414
Gnomad NFE
AF:
0.520
Gnomad OTH
AF:
0.500
GnomAD4 exome
AF:
0.522
AC:
703288
AN:
1347310
Hom.:
184643
AF XY:
0.521
AC XY:
351341
AN XY:
674262
show subpopulations
African (AFR)
AF:
0.489
AC:
15070
AN:
30794
American (AMR)
AF:
0.513
AC:
21766
AN:
42462
Ashkenazi Jewish (ASJ)
AF:
0.474
AC:
12000
AN:
25324
East Asian (EAS)
AF:
0.608
AC:
23217
AN:
38160
South Asian (SAS)
AF:
0.489
AC:
39715
AN:
81152
European-Finnish (FIN)
AF:
0.575
AC:
29801
AN:
51848
Middle Eastern (MID)
AF:
0.408
AC:
2267
AN:
5562
European-Non Finnish (NFE)
AF:
0.522
AC:
530380
AN:
1015616
Other (OTH)
AF:
0.516
AC:
29072
AN:
56392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
16217
32435
48652
64870
81087
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
14870
29740
44610
59480
74350
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.517
AC:
78659
AN:
152022
Hom.:
20438
Cov.:
33
AF XY:
0.521
AC XY:
38727
AN XY:
74302
show subpopulations
African (AFR)
AF:
0.501
AC:
20763
AN:
41478
American (AMR)
AF:
0.530
AC:
8097
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.472
AC:
1639
AN:
3470
East Asian (EAS)
AF:
0.570
AC:
2947
AN:
5166
South Asian (SAS)
AF:
0.478
AC:
2301
AN:
4810
European-Finnish (FIN)
AF:
0.573
AC:
6044
AN:
10552
Middle Eastern (MID)
AF:
0.414
AC:
121
AN:
292
European-Non Finnish (NFE)
AF:
0.520
AC:
35305
AN:
67952
Other (OTH)
AF:
0.498
AC:
1050
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
1972
3944
5917
7889
9861
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
702
1404
2106
2808
3510
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.515
Hom.:
94699
Bravo
AF:
0.511
Asia WGS
AF:
0.520
AC:
1809
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:12Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:4Other:1
Jan 12, 2015
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance:Benign
Review Status:reviewed by expert panel
Collection Method:curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.549 (Asian), 0.502 (African), 0.5383 (European), derived from 1000 genomes (2012-04-30). -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breast Cancer Information Core (BIC) (BRCA2)
Significance:not provided
Review Status:no classification provided
Collection Method:clinical testing

- -

-
GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 09, 2014
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:4
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Nov 01, 2017
GeneKor MSA
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Hereditary cancer-predisposing syndrome Benign:1
Nov 19, 2014
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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:1
Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1
Apr 19, 2022
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.88
CADD
Benign
0.98
DANN
Benign
0.47
PhyloP100
-1.2
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs4942486; hg19: chr13-32953388; COSMIC: COSV66457232; COSMIC: COSV66457232; API