rs11571662

Variant names:

• chr13-32341387-C-A
• rs11571662
• NM_000059.4:c.6841+191C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000059.4(BRCA2):​c.6841+191C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 151,844 control chromosomes in the GnomAD database, including 6,230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.28 (6230 hom., cov: 31)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.479
• Publications: 9 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):

• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 13-32341387-C-A is Benign according to our data. Variant chr13-32341387-C-A is described in ClinVar as Benign. ClinVar VariationId is 209691.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.6841+191C>A		intron	N/A	NP_000050.3
	BRCA2	NM_001432077.1		c.6841+191C>A		intron	N/A	NP_001419006.1
	BRCA2	NM_001406720.1		c.6841+191C>A		intron	N/A	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.6841+191C>A		intron	N/A	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.6841+191C>A		intron	N/A	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.6472+191C>A		intron	N/A	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.283 AC: 42879 AN: 151726 Hom.: 6234 Cov.: 31

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.176

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.275

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.282 AC: 42869 AN: 151844 Hom.: 6230 Cov.: 31 AF XY: 0.284 AC XY: 21057 AN XY: 74196

African (AFR) AF: 0.230 AC: 9509 AN: 41404

American (AMR) AF: 0.223 AC: 3396 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1061 AN: 3464

East Asian (EAS) AF: 0.398 AC: 2058 AN: 5170

South Asian (SAS) AF: 0.290 AC: 1395 AN: 4810

European-Finnish (FIN) AF: 0.317 AC: 3335 AN: 10504

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21295 AN: 67920

Other (OTH) AF: 0.272 AC: 573 AN: 2106

Alfa AF: 0.305 Hom.: 961

Bravo AF: 0.272

Asia WGS AF: 0.278 AC: 970 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Breast-ovarian cancer, familial, susceptibility to, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.47
DANN	Benign	0.31
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11571662; hg19: chr13-32915524;