chr13-32354863-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000059.4(BRCA2):​c.7010C>G​(p.Thr2337Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. 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. T2337I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

BRCA2
NM_000059.4 missense, splice_region

Scores

1
6
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.962
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.7010C>G p.Thr2337Arg missense_variant, splice_region_variant 14/27 ENST00000380152.8 NP_000050.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.7010C>G p.Thr2337Arg missense_variant, splice_region_variant 14/275 NM_000059.4 ENSP00000369497 A2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.098
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
27
DANN
Uncertain
0.99
Eigen
Benign
0.11
Eigen_PC
Benign
0.018
FATHMM_MKL
Benign
0.32
N
M_CAP
Pathogenic
0.35
D
MetaRNN
Uncertain
0.44
T;T
MetaSVM
Uncertain
-0.065
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-1.4
N;N
REVEL
Uncertain
0.44
Sift
Benign
0.069
T;T
Sift4G
Benign
0.17
T;T
Vest4
0.39
MutPred
0.18
Loss of ubiquitination at K2339 (P = 0.0289);Loss of ubiquitination at K2339 (P = 0.0289);
MVP
0.92
MPC
0.094
ClinPred
0.90
D
GERP RS
3.9
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.79
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.79
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-32929000; API