rs80359759

chr13-32394831-AG-A

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.9401del(p.Gly3134AlafsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. G3134G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 0.770

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]

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 13-32394831-AG-A is Pathogenic according to our data. Variant chr13-32394831-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 38239.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32394831-AG-A is described in Lovd as [Pathogenic]. Variant chr13-32394831-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9401del	p.Gly3134AlafsTer29	frameshift_variant	25/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9401del	p.Gly3134AlafsTer29	frameshift_variant	25/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5

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	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 27, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	The c.9401del (p.Gly3134Alafs*29) variant in the BRCA2 gene was reported in patients from the Italian Consortium for Hereditary Breast and Ovarian Cancer [PMID 14531499]. This variant has been reported as pathogenic in ClinVar by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/38239). This one bp deletion in exon 25 results in a frameshift and the creation of a premature stop codon. This variant is thus predicted to result in a loss of function of the protein. This variant has not been observed in the ExAC population database. This variant is thus classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 13, 2018	The p.Gly3134AlafsX29 variant in BRCA2 has been reported in multiple families wi th breast and/or ovarian cancer (HBOC; Aretini 2003, Zhong 2016, Rebbeck 2018) a nd was absent from population databases. This variant is predicted to cause a fr ameshift, which alters the protein?s amino acid sequence beginning at position 3 134 and leads to a premature termination codon 29 amino acids downstream. This a lteration is then predicted to lead to a truncated or absent protein. Heterozygo us loss of function of the BRCA2 gene is an established disease mechanism in HBO C. In addition, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000301388.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon absence from controls, proband count, and the predict ed impact on protein. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 02, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 38239). This variant is also known as 9629delG. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 14531499, 27257965). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly3134Alafs*29) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Breast neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University

Nov 01, 2015

- -

Familial cancer of breast Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

-

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2022

The c.9401delG pathogenic mutation, located in coding exon 24 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 9401, causing a translational frameshift with a predicted alternate stop codon (p.G3134Afs*29). This mutation has been reported in numerous probands from hereditary breast and/or ovarian cancer families across multiple ethnicities (Aretini P et al. Breast Cancer Res. Treat., 2003 Sep;81:71-9; Kwong A et al. J Mol Diagn, 2016 Jul;18:580-94; Rebbeck TR et al. Breast Cancer Res., 2016 Nov;18:112; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481). Of note, this alteration is also designated as 9629delG in published literature. 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. -

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: rs80359759; hg19: chr13-32968968;