rs3092990

Variant names:

• chr13-32364618-C-CT
• rs3092990
• NM_000059.4:c.8331+1086dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000059.4(BRCA2):​c.8331+1086dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 152,130 control chromosomes in the GnomAD database, including 4,296 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.22 (4296 hom., cov: 26)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: -1.18
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 13-32364618-C-CT is Benign according to our data. Variant chr13-32364618-C-CT is described in ClinVar as Benign. ClinVar VariationId is 209783.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8331+1086dupT		intron_variant	Intron 18 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8331+1085_8331+1086insT		intron_variant	Intron 18 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7962+1085_7962+1086insT		intron_variant	Intron 18 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*389+1085_*389+1086insT		intron_variant	Intron 17 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34120 AN: 152012 Hom.: 4294 Cov.: 26

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.252

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

GnomAD4 genome AF: 0.224 AC: 34135 AN: 152130 Hom.: 4296 Cov.: 26 AF XY: 0.223 AC XY: 16603 AN XY: 74378

African (AFR) AF: 0.122 AC: 5063 AN: 41514

American (AMR) AF: 0.288 AC: 4396 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1361 AN: 3468

East Asian (EAS) AF: 0.183 AC: 952 AN: 5190

South Asian (SAS) AF: 0.289 AC: 1393 AN: 4824

European-Finnish (FIN) AF: 0.204 AC: 2159 AN: 10574

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17916 AN: 67964

Other (OTH) AF: 0.257 AC: 542 AN: 2112

Alfa AF: 0.249 Hom.: 604

Bravo AF: 0.226

Asia WGS AF: 0.257 AC: 893 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 0.19 (Asian), 0.1 (African), 0.25 (European), derived from 1000 genomes (2012-04-30). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
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: rs3092990; hg19: chr13-32938755;