NM_000059.4:c.7007+1298A>C

Variant names:

• chr13-32348194-A-C
• rs11571686
• NM_000059.4:c.7007+1298A>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.7007+1298A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0866 in 152,158 control chromosomes in the GnomAD database, including 785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.087 (785 hom., cov: 31)
• Consequence: BRCA2 NM_000059.4 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.0150
• Publications: 13 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 13-32348194-A-C is Benign according to our data. Variant chr13-32348194-A-C is described in ClinVar as Benign. ClinVar VariationId is 209727.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7007+1298A>C		intron_variant	Intron 13 of 26	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7007+1298A>C		intron_variant	Intron 13 of 26	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6638+1298A>C		intron_variant	Intron 13 of 26	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7007+1298A>C		intron_variant	Intron 12 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 13174 AN: 152040 Hom.: 786 Cov.: 31

Gnomad AFR AF: 0.0201

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0611

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0634

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.0705

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.0906

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

GnomAD4 genome AF: 0.0866 AC: 13170 AN: 152158 Hom.: 785 Cov.: 31 AF XY: 0.0911 AC XY: 6780 AN XY: 74388

African (AFR) AF: 0.0201 AC: 835 AN: 41568

American (AMR) AF: 0.0609 AC: 931 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3470

East Asian (EAS) AF: 0.0635 AC: 328 AN: 5164

South Asian (SAS) AF: 0.109 AC: 525 AN: 4814

European-Finnish (FIN) AF: 0.183 AC: 1935 AN: 10562

Middle Eastern (MID) AF: 0.0724 AC: 21 AN: 290

European-Non Finnish (NFE) AF: 0.117 AC: 7933 AN: 67994

Other (OTH) AF: 0.0897 AC: 189 AN: 2108

Alfa AF: 0.0931 Hom.: 853

Bravo AF: 0.0727

Asia WGS AF: 0.0630 AC: 221 AN: 3474

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 0.0542 (Asian), 0.1319 (European), derived from 1000 genomes (2012-04-30). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.71
PhyloP100		-0.015
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: rs11571686; hg19: chr13-32922331;