13-32332938-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000059.4(BRCA2):​c.1460C>T​(p.Ala487Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,607,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A487E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

1
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0850
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA2NM_000059.4 linkc.1460C>T p.Ala487Val missense_variant 10/27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.1460C>T p.Ala487Val missense_variant 10/275 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.1091C>T p.Ala364Val missense_variant 10/271 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.1460C>T non_coding_transcript_exon_variant 9/262 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000410
AC:
1
AN:
243790
Hom.:
0
AF XY:
0.00000759
AC XY:
1
AN XY:
131754
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000352
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1455122
Hom.:
0
Cov.:
35
AF XY:
0.00000276
AC XY:
2
AN XY:
723428
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000238
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152144
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
14
DANN
Benign
0.050
Eigen
Benign
-0.98
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.046
N
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.10
T;T
MetaSVM
Benign
-0.86
T
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.31
N;N
REVEL
Benign
0.28
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Vest4
0.37
MutPred
0.18
Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP
0.83
MPC
0.023
ClinPred
0.011
T
GERP RS
-0.17
gMVP
0.079

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.44
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.44
Position offset: -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: rs56390402; hg19: chr13-32907075; COSMIC: COSV66458810; API