Genetic Variant BRCA2:c.1909+1G>A (chr13-32333388-G-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_StrongPS3PM2PP5_Very_Strong

The NM_000059.4(BRCA2):c.1909+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000686 in 1,457,272 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 (★★). ClinVar reports functional evidence for this variant: "SCV000184540: RNA assays have shown this alteration to cause the skipping of coding exons 8 and 9 (total exons 9 and 10 in literature), which leads to a transcript that will undergo nonsense-mediated decay (Ambry internal data; Montalban G. et al J Med Genet 2019 02;56(2):63-74.); SCV000688732: A functional study reports exon 9-10 skipping in 63.2% of transcripts resulting in a premature stop signal. PMID:26296696, 26681678, 26845104, 28495237, 30103829, 30472649; SCV000296672: This variant has also been reported to have a deleterious effect on BRCA2 mRNA splicing (PMID:31343793 (2019)).; SCV004564410: "functional studies suggest this variant causes skipping of exons 9 and 10, leading to a frameshift." (Montalban G et al. Incorporation of semi-quantitative analysis of splicing alterations for the clinical interpretation of variants in BRCA1 and BRCA2 genes. Hum Mutat. 2019 Dec;40(12):2296-2317. PMID:31343793.); SCV000260614: Studies have shown that disruption of this splice site results in skipping of exons 9-10, and produces a non-functional protein and/or introduces a premature termination codon (PMID:31343793; internal data).".

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 5.70

Publications

8 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):

BRCA2-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
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

BRCA2 links:

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, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.10880374 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000184540: RNA assays have shown this alteration to cause the skipping of coding exons 8 and 9 (total exons 9 and 10 in literature), which leads to a transcript that will undergo nonsense-mediated decay (Ambry internal data; Montalban G. et al J Med Genet 2019 02;56(2):63-74.); SCV000688732: A functional study reports exon 9-10 skipping in 63.2% of transcripts resulting in a premature stop signal. PMID: 26296696, 26681678, 26845104, 28495237, 30103829, 30472649; SCV000296672: This variant has also been reported to have a deleterious effect on BRCA2 mRNA splicing (PMID: 31343793 (2019)).; SCV004564410: "functional studies suggest this variant causes skipping of exons 9 and 10, leading to a frameshift." (Montalban G et al. Incorporation of semi-quantitative analysis of splicing alterations for the clinical interpretation of variants in BRCA1 and BRCA2 genes. Hum Mutat. 2019 Dec;40(12):2296-2317. PMID: 31343793.); SCV000260614: Studies have shown that disruption of this splice site results in skipping of exons 9-10, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 31343793; internal data).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-32333388-G-A is Pathogenic according to our data. Variant chr13-32333388-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 141283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BRCA2	NM_000059.4	MANE Select	c.1909+1G>A	splice_donor intron	N/A	NP_000050.3	A0A7P0T9D7
BRCA2	NM_001432077.1		c.1909+1G>A	splice_donor intron	N/A	NP_001419006.1	A0A7P0T9D7
BRCA2	NM_001406720.1		c.1909+1G>A	splice_donor intron	N/A	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.1909+1G>A	splice_donor intron	N/A	ENSP00000369497.3	P51587
BRCA2	ENST00000544455.6	TSL:1	c.1909+1G>A	splice_donor intron	N/A	ENSP00000439902.1	P51587
BRCA2	ENST00000530893.7	TSL:1	c.1540+1G>A	splice_donor intron	N/A	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724414

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33296

American (AMR)

AF:

0.00

AC:

AN:

44320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

84466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111088

Other (OTH)

AF:

0.00

AC:

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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.:

Alfa

AF:

0.0000101

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 2 (3)

Hereditary breast ovarian cancer syndrome (3)

Hereditary cancer-predisposing syndrome (3)

not provided (3)

Breast-ovarian cancer, familial, susceptibility to, 1 (1)

Familial cancer of breast (1)

Gastric cancer (1)

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

PhyloP100

5.7

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.99

Position offset: -1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over