13-32316090-G-T

Variant names:

• chr13-32316090-G-T
• rs9567552
• NM_000059.4:c.-39-332G>T

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.-39-332G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 152,126 control chromosomes in the GnomAD database, including 4,017 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.23 (4017 hom., cov: 33)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 0.830
• Publications: 19 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=-0.9).
• BP6: Variant 13-32316090-G-T is Benign according to our data. Variant chr13-32316090-G-T is described in ClinVar as Benign. ClinVar VariationId is 209603.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.336 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.-39-332G>T		intron	N/A	NP_000050.3
	BRCA2	NM_001432077.1		c.-39-332G>T		intron	N/A	NP_001419006.1
	BRCA2	NM_001406720.1		c.-39-332G>T		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.-39-332G>T		intron	N/A	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.-39-332G>T		intron	N/A	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.-404-332G>T		intron	N/A	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34430 AN: 152006 Hom.: 4018 Cov.: 33

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.227

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

GnomAD4 genome AF: 0.226 AC: 34428 AN: 152126 Hom.: 4017 Cov.: 33 AF XY: 0.224 AC XY: 16633 AN XY: 74354

African (AFR) AF: 0.196 AC: 8146 AN: 41474

American (AMR) AF: 0.188 AC: 2870 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 840 AN: 3466

East Asian (EAS) AF: 0.350 AC: 1814 AN: 5186

South Asian (SAS) AF: 0.253 AC: 1219 AN: 4816

European-Finnish (FIN) AF: 0.180 AC: 1912 AN: 10596

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16929 AN: 67980

Other (OTH) AF: 0.225 AC: 475 AN: 2112

Alfa AF: 0.230 Hom.: 5197

Bravo AF: 0.226

Asia WGS AF: 0.236 AC: 819 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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 0.3374 (Asian), 0.128 (African), 0.2124 (European), derived from 1000 genomes (2012-04-30).

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.7
DANN	Benign	0.60
PhyloP100		0.83
PromoterAI		0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs9567552; hg19: chr13-32890227;