rs206340

Variant names:

• chr13-32391173-G-A
• rs206340
• NM_000059.4:c.9257-3516G>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.9257-3516G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,046 control chromosomes in the GnomAD database, including 3,480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.21 (3480 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 0.254
• Publications: 12 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 13-32391173-G-A is Benign according to our data. Variant chr13-32391173-G-A is described in ClinVar as Benign. ClinVar VariationId is 209893.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9257-3516G>A		intron_variant	Intron 24 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9257-3516G>A		intron_variant	Intron 24 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8888-3516G>A		intron_variant	Intron 24 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1315-3516G>A		intron_variant	Intron 23 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32235 AN: 151928 Hom.: 3478 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.246

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.212

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

GnomAD4 genome AF: 0.212 AC: 32240 AN: 152046 Hom.: 3480 Cov.: 32 AF XY: 0.211 AC XY: 15671 AN XY: 74330

African (AFR) AF: 0.216 AC: 8963 AN: 41472

American (AMR) AF: 0.169 AC: 2591 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 479 AN: 3468

East Asian (EAS) AF: 0.247 AC: 1279 AN: 5180

South Asian (SAS) AF: 0.231 AC: 1111 AN: 4814

European-Finnish (FIN) AF: 0.222 AC: 2346 AN: 10548

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.216 AC: 14696 AN: 67964

Other (OTH) AF: 0.211 AC: 444 AN: 2108

Alfa AF: 0.213 Hom.: 9410

Bravo AF: 0.211

Asia WGS AF: 0.210 AC: 731 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:1

Jan 12, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.2587 (Asian), 0.2195 (African), 0.2137 (European), derived from 1000 genomes (2012-04-30). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.9
DANN	Benign	0.77
PhyloP100		0.25
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: rs206340; hg19: chr13-32965310;