13-32396599-G-C

Variant names:

• chr13-32396599-G-C
• rs1012129
• NM_000059.4:c.9502-299G>C

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.9502-299G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 151,958 control chromosomes in the GnomAD database, including 20,412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.52 (20412 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -1.50
• Publications: 7 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=-0.92).
• BP6: Variant 13-32396599-G-C is Benign according to our data. Variant chr13-32396599-G-C is described in ClinVar as Benign. ClinVar VariationId is 209963.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9502-299G>C		intron_variant	Intron 25 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9502-299G>C		intron_variant	Intron 25 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9133-299G>C		intron_variant	Intron 25 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1560-299G>C		intron_variant	Intron 24 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78511 AN: 151842 Hom.: 20393 Cov.: 32

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.574

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.500

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

GnomAD4 genome AF: 0.517 AC: 78580 AN: 151958 Hom.: 20412 Cov.: 32 AF XY: 0.521 AC XY: 38685 AN XY: 74258

African (AFR) AF: 0.499 AC: 20692 AN: 41448

American (AMR) AF: 0.529 AC: 8084 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1640 AN: 3466

East Asian (EAS) AF: 0.570 AC: 2946 AN: 5166

South Asian (SAS) AF: 0.478 AC: 2305 AN: 4818

European-Finnish (FIN) AF: 0.574 AC: 6048 AN: 10538

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35300 AN: 67934

Other (OTH) AF: 0.498 AC: 1050 AN: 2108

Alfa AF: 0.512 Hom.: 2378

Bravo AF: 0.510

Asia WGS AF: 0.521 AC: 1811 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 0.549 (Asian), 0.502 (African), 0.5383 (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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.055
DANN	Benign	0.66
PhyloP100		-1.5
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: rs1012129; hg19: chr13-32970736;