chr13-32340300-GT-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM3_StrongPM5_StrongPVS1

This summary comes from the ClinGen Evidence Repository: The c.5946del variant in BRCA2 is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 22 of the frameshift, or amino acid 2003 (p.Ser1982ArgfsTer22). This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 11 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA2, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA2 exon 11 (PM5_Strong (PTC)). This variant has been detected in 6 individuals with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least two clinical features of FA (physical features, pathology findings and cancer diagnosis ≤5yr) and confirmed chromosome breakage, are seen in these individuals. 6 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, and confirmed to be in trans. Total points equated to 8 (PM3_Strong met; PMIDs: 14559878, 15516848, 16825431, 19530235). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PM3_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023403/MONDO:0012933/097

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:76O:3

Conservation

PhyloP100: 2.83

Publications

287 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

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PM5

For more information check the summary or visit ClinGen Evidence Repository.

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	HGVSp	Effect	Exon Rank	Protein
BRCA2	NM_000059.4	MANE Select	c.5946delT	p.Ser1982ArgfsTer22	frameshift	Exon 11 of 27	NP_000050.3
BRCA2	NM_001432077.1		c.5946delT	p.Ser1982ArgfsTer22	frameshift	Exon 11 of 27	NP_001419006.1
BRCA2	NM_001406720.1		c.5946delT	p.Ser1982ArgfsTer22	frameshift	Exon 11 of 27	NP_001393649.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.5946delT	p.Ser1982ArgfsTer22	frameshift	Exon 11 of 27	ENSP00000369497.3
BRCA2	ENST00000544455.6	TSL:1	c.5946delT	p.Ser1982ArgfsTer22	frameshift	Exon 11 of 27	ENSP00000439902.1
BRCA2	ENST00000530893.7	TSL:1	c.5577delT	p.Ser1859ArgfsTer22	frameshift	Exon 11 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000291

AC:

AN:

250700

AF XY:

0.000236

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00586

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000969

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000136

AC:

199

AN:

1461720

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00528

AC:

138

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

1111916

Other (OTH)

AF:

0.000513

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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

AF:

0.000171

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00577

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000738

Hom.:

Bravo

AF:

0.000110

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 2 (29)

not provided (18)

Hereditary breast ovarian cancer syndrome (11)

Hereditary cancer-predisposing syndrome (6)

Familial cancer of breast (3)

BRCA2-related cancer predisposition (2)

BRCA2-related disorder (2)

Breast and/or ovarian cancer (1)

Breast neoplasm (1)

Endometrial carcinoma (1)

Fanconi anemia complementation group D1 (1)

Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 (1)

Ovarian neoplasm (1)

Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 (1)

Pancreatic cancer, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.8

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over