rs81002798

Variant names:

• chr13-32370558-G-A
• rs81002798
• NM_000059.4:c.8487+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32370558-G-A
• chr13-32370558-G-C
• chr13-32370558-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8487+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 0.000000686 in 1,457,402 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 Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000186016: Multiple splicing assays have shown that this alteration leads to complete skipping of coding exon 18, resulting in a predicted in-frame deletion of 52 amino acid residues in a functionally important region of the BRCA2 protein (Ambry internal data" and additional evidence is available in ClinVar. The gene BRCA2 is included in the ClinGen Criteria Specification Registry.

• 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 reviewed by expert panel P:17 O:1
• Conservation: PhyloP100: 9.92
• Publications: 24 publications found

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

ACMG classification

Specifications for BRCA2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.015209125 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000186016: Multiple splicing assays have shown that this alteration leads to complete skipping of coding exon 18, resulting in a predicted in-frame deletion of 52 amino acid residues in a functionally important region of the BRCA2 protein (Ambry internal data; Mesman RLS et al. Genet Med 2020 08;22(8):1355-1365; Chen X et al. Hum. Mutat. 2006 May;27:427-35; Acedo A et al. Breast Cancer Res. 2012 May 25;14:R87; Agata S et al. Cancer Genet. Cytogenet. 2003 Mar;141:175-6).; SCV000689129: Functional RNA studies have shown that this variant results in the skipping of exon 19, causing an in-frame deletion of 52 amino acids within the essential DNA binding domain of BRCA2 protein (PMID: 12606139, 16619214, 22632462).; SCV002049292: Functional assays demonstrate skipping of exon 19 (Agata 2003, Chen 2006). PMID: 12606139. PMID: 16619214.; SCV000073547: Studies have shown that disruption of this splice site results in skipping of exon 19, but is expected to preserve the integrity of the reading-frame (PMID: 12606139, 16619214, 22632462; internal data).; SCV000271334: "In vitro functional studies provide evidence that the c.8487+1G>A variant impacts splicing (Agata 2003, Acedo 2012, Chen 2006)."; SCV000918865: The variant was supported by experimental evidence which causes skipping of exon 19 leading to an abnormal protein product (p.Ille2778_Gln2829del)(Chen_2006, Agata_2003).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32370558-G-A is Pathogenic according to our data. Variant chr13-32370558-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 52602.Status of the report is reviewed_by_expert_panel, 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.8487+1G>A		splice_donor intron	N/A	NP_000050.3	A0A7P0T9D7
	BRCA2	NM_001432077.1		c.8487+1G>A		splice_donor intron	N/A	NP_001419006.1	A0A7P0T9D7
	BRCA2	NM_001406720.1		c.8487+1G>A		splice_donor intron	N/A	NP_001393649.1	A0A8V8TPZ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.8487+1G>A		splice_donor intron	N/A	ENSP00000369497.3	P51587
	BRCA2	ENST00000544455.6	TSL:1	c.8487+1G>A		splice_donor intron	N/A	ENSP00000439902.1	P51587
	BRCA2	ENST00000530893.7	TSL:1	c.8118+1G>A		splice_donor intron	N/A	ENSP00000499438.2	A0A590UJI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457402 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725408

African (AFR) AF: 0.00 AC: 0 AN: 33368

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107964

Other (OTH) AF: 0.00 AC: 0 AN: 60250

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Breast-ovarian cancer, familial, susceptibility to, 2 (6)
4	-	-	Hereditary breast ovarian cancer syndrome (4)
3	-	-	Hereditary cancer-predisposing syndrome (3)
3	-	-	not provided (3)
1	-	-	Familial cancer of breast (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.9
GERP RS		5.2
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: -1

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

Other links and lift over

dbSNP: rs81002798; hg19: chr13-32944695;