GeneBe

rs1555283155

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4BP6

The NM_000059.4(BRCA2):​c.3300C>A​(p.Asn1100Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1100I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

BRCA2
NM_000059.4 missense

Scores

1
1
13

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.711

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3603375).
BP6
Variant 13-32337655-C-A is Benign according to our data. Variant chr13-32337655-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 489754.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
BRCA2
NM_000059.4
MANE Select
c.3300C>Ap.Asn1100Lys
missense
Exon 11 of 27NP_000050.3
BRCA2
NM_001432077.1
c.3300C>Ap.Asn1100Lys
missense
Exon 11 of 27NP_001419006.1
BRCA2
NM_001406720.1
c.3300C>Ap.Asn1100Lys
missense
Exon 11 of 27NP_001393649.1

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
BRCA2
ENST00000380152.8
TSL:5 MANE Select
c.3300C>Ap.Asn1100Lys
missense
Exon 11 of 27ENSP00000369497.3
BRCA2
ENST00000544455.6
TSL:1
c.3300C>Ap.Asn1100Lys
missense
Exon 11 of 27ENSP00000439902.1
BRCA2
ENST00000530893.7
TSL:1
c.2931C>Ap.Asn977Lys
missense
Exon 11 of 27ENSP00000499438.2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1436234
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
712140
African (AFR)
AF:
0.00
AC:
0
AN:
32118
American (AMR)
AF:
0.00
AC:
0
AN:
39854
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24812
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39434
South Asian (SAS)
AF:
0.00
AC:
0
AN:
81642
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52592
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5634
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1100988
Other (OTH)
AF:
0.00
AC:
0
AN:
59160
GnomAD4 genome
Cov.:
32

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity
Revision:criteria provided, conflicting classifications
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
1
1
Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
15
DANN
Uncertain
0.98
Eigen
Benign
-0.83
Eigen_PC
Benign
-0.92
FATHMM_MKL
Benign
0.14
N
M_CAP
Benign
0.077
D
MetaRNN
Benign
0.36
T
MetaSVM
Benign
-0.87
T
PhyloP100
-0.71
PrimateAI
Benign
0.45
T
PROVEAN
Pathogenic
-5.1
D
REVEL
Benign
0.18
Sift
Benign
0.11
T
Sift4G
Benign
0.29
T
Vest4
0.51
MutPred
0.38
Gain of ubiquitination at N1100 (P = 0.0014)
MVP
0.75
MPC
0.11
ClinPred
0.96
D
GERP RS
-2.1
gMVP
0.34
Mutation Taster
=78/22
polymorphism

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: rs1555283155; hg19: chr13-32911792; API