rs81002883

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9256+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.27

Publications

6 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: Pathogenic. The variant received 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-32380146-G-A is Pathogenic according to our data. Variant chr13-32380146-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.9256+1G>A splice_donor_variant, intron_variant Intron 24 of 26 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.9256+1G>A splice_donor_variant, intron_variant Intron 24 of 26 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.8887+1G>A splice_donor_variant, intron_variant Intron 24 of 26 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.*1314+1G>A splice_donor_variant, intron_variant Intron 23 of 25 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459038
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
725806
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33300
American (AMR)
AF:
0.00
AC:
0
AN:
44348
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26072
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39646
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85666
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5752
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1110586
Other (OTH)
AF:
0.00
AC:
0
AN:
60268
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
33
Alfa
AF:
0.0000405
Hom.:
0

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3
Apr 26, 2018
Counsyl
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 29, 2002
Breast Cancer Information Core (BIC) (BRCA2)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

BRCA2-related disorder Pathogenic:1
Apr 26, 2024
PreventionGenetics, part of Exact Sciences
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

The BRCA2 c.9256+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also known as IVS24+1G>A, has been reported in multiple individuals with breast and/or ovarian cancer (Table 1, Claes et al. 2003. PubMed ID: 12759930; Table S1, Rebbeck et al. 2018. PubMed ID: 29446198). RT-PCR studies suggest this variant impacts mRNA splicing leading to exon 24 skipping (Figure 1, Acedo et al. 2012. PubMed ID: 22632462; Figure 3, Mesman et al. 2020. PubMed ID: 32398771). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52787). Variants that disrupt the consensus splice donor site in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1
Mar 21, 2024
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9584+1G>A and IVS24+1G>A; This variant is associated with the following publications: (PMID: 29446198, 25525159, 25382762, 32398771, 22632462, 30078507, 12759930, 15026808, 31742824) -

Hereditary cancer-predisposing syndrome Pathogenic:1
Apr 17, 2024
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.9256+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 23 of the BRCA2 gene. This alteration was classified in one study as a class 4 or 5 alteration based on a multifactorial 5-tier system using both bioinformatics information and splicing assay information reviewed in the literature (Walker LC et al. Hum. Mutat. 2013 Oct;34(10):1424-31). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have shown that this alteration leads to skipping of coding exon 23, leading to a frameshift and premature stop codon (Ambry internal data; Claes K et al. Genes Chromosomes Cancer 2003 Jul;37(3):314-20; Acedo A et al. Hum. Mutat. 2015 Feb;36(2):210-21). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1
Sep 18, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Disruption of this splice site has been observed in individual(s) with breast and prostate cancer (PMID: 12759930). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 24 and introduces a premature termination codon (PMID: 12759930, 22632462, 25382762). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 52787). This variant is also known as IVS24+1G>A. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 24 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
0.99
D
PhyloP100
9.3
GERP RS
5.5
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
Splicevardb
3.0
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DL_spliceai
1.0
Position offset: -1

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

Publications

Other links and lift over

dbSNP: rs81002883; hg19: chr13-32954283; API