rs80359764

Positions:

• chr13-32394884-AAG-A
• chr13-32394884-AAG-AAGAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9455_9456delAG​(p.Glu3152fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 3.79

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32394884-AAG-A is Pathogenic according to our data. Variant chr13-32394884-AAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 52840.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32394884-AAG-A is described in Lovd as [Pathogenic]. Variant chr13-32394884-AAG-A is described in Lovd as [Pathogenic]. Variant chr13-32394884-AAG-A is described in Lovd as [Pathogenic]. Variant chr13-32394884-AAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9455_9456delAG	p.Glu3152fs	frameshift_variant	25/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9455_9456delAG	p.Glu3152fs	frameshift_variant	25/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9086_9087delAG	p.Glu3029fs	frameshift_variant	25/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1513_*1514delAG		non_coding_transcript_exon_variant	24/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1513_*1514delAG		3_prime_UTR_variant	24/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 27, 2021	The c.9455_9456delAG pathogenic mutation, located in coding exon 24 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 9455 to 9456, causing a translational frameshift with a predicted alternate stop codon (p.E3152Gfs*15). This mutation has been identified in several hereditary breast and ovarian cancer (HBOC) families (Pinto P et al. Breast Cancer Res Treat, 2016 Sep;159:245-56; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Capone GL et al. J Mol Diagn, 2018 01;20:87-94; Guindalini RSC et al. Clin Cancer Res, 2019 03;25:1786-1794; Laitman Y et al. Hum Mutat, 2019 11;40:e1-e23; Incorvaia L et al. Ther Adv Med Oncol, 2020 Dec;12:1758835920975326). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2021	This variant deletes 2 nucleotides in exon 25 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in two individuals affected with breast cancer (PMID: 10923033, 33403015) and has been identified in 2 families among the CIMBA participants (PMID: 29446198, 31209999). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Sep 15, 2021

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Jan 31, 2014

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs80359764; hg19: chr13-32969021;