13-32319654-A-G

Variant names:

• chr13-32319654-A-G
• rs9534174
• NM_000059.4:c.316+329A>G

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.316+329A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 152,070 control chromosomes in the GnomAD database, including 22,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.54 (22558 hom., cov: 33)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: -1.66
• Publications: 11 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=-0.91).
• BP6: Variant 13-32319654-A-G is Benign according to our data. Variant chr13-32319654-A-G is described in ClinVar as Benign. ClinVar VariationId is 209933.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 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.316+329A>G		intron	N/A	NP_000050.3
	BRCA2	NM_001432077.1		c.316+329A>G		intron	N/A	NP_001419006.1
	BRCA2	NM_001406720.1		c.316+329A>G		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.316+329A>G		intron	N/A	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.316+329A>G		intron	N/A	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.-54+329A>G		intron	N/A	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82758 AN: 151952 Hom.: 22537 Cov.: 33

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.531

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

GnomAD4 genome AF: 0.545 AC: 82821 AN: 152070 Hom.: 22558 Cov.: 33 AF XY: 0.548 AC XY: 40718 AN XY: 74330

African (AFR) AF: 0.567 AC: 23508 AN: 41474

American (AMR) AF: 0.530 AC: 8108 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 1786 AN: 3466

East Asian (EAS) AF: 0.582 AC: 3006 AN: 5168

South Asian (SAS) AF: 0.522 AC: 2515 AN: 4822

European-Finnish (FIN) AF: 0.587 AC: 6201 AN: 10568

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.530 AC: 36025 AN: 67970

Other (OTH) AF: 0.528 AC: 1115 AN: 2112

Alfa AF: 0.536 Hom.: 3815

Bravo AF: 0.540

Asia WGS AF: 0.533 AC: 1852 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 0.5629 (Asian), 0.5467 (African), 0.5317 (European), derived from 1000 genomes (2012-04-30).

Hereditary cancer-predisposing syndrome Benign:1

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.29
DANN	Benign	0.41
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9534174; hg19: chr13-32893791;