chr13-32344575-A-T

Variant names:

• chr13-32344575-A-T
• rs876661261
• NM_000059.4:c.6859A>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PVS1

This summary comes from the ClinGen Evidence Repository: The c.6859A>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual arginine at amino acid 2287 (p.(Arg2287Ter)). This variant is present in gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Nonsense of exon 12 variant predicted to cause a premature stop codon in biologically-relevant-exon 12/27 leading to nonsense mediated decay (PVS1 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID:32046981) (PS3 met).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PS3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA387792666/MONDO:0700269/097

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 3.87
• Publications: 5 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6859A>T	p.Arg2287*	stop_gained	Exon 12 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6859A>T	p.Arg2287*	stop_gained	Exon 12 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6490A>T	p.Arg2164*	stop_gained	Exon 12 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6859A>T		non_coding_transcript_exon_variant	Exon 11 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:2

Oct 08, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic, low penetrance

Review Status: no assertion criteria provided

Collection Method: curation

Variant found in patients with FA therefore may be hypomorphic; According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: PVS1 (very strong pathogenic): Table 4, PM3 (supporting pathogenic): Ambry Genetics: This variant has been confirmed to be in trans with a BRCA2 pathogenic variant in an individual diagnosed with clinical features of Fanconi anemia (external communication). -

Feb 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg2287*) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 575178). For these reasons, this variant has been classified as Pathogenic. -

BRCA2-related cancer predisposition Pathogenic:1

May 23, 2025

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.6859A>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual arginine at amino acid 2287 (p.(Arg2287Ter)). This variant is present in gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Nonsense of exon 12 variant predicted to cause a premature stop codon in biologically-relevant-exon 12/27 leading to nonsense mediated decay (PVS1 met). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID:32046981) (PS3 met). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PS3). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 10, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R2287* variant (also known as c.6859A>T), located in coding exon 11 of the BRCA2 gene, results from an A to T substitution at nucleotide position 6859. This changes the amino acid from an arginine to a stop codon within coding exon 11. This variant has been confirmed to be in trans with a BRCA2 pathogenic variant in an individual diagnosed with clinical features of Fanconi anemia (external communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, this variant occurs in an exon that is absent in biologically relevant transcripts (referred to as exon 12 in the literature; Li L et al. Hum. Mutat. 2009 Nov;30(11):1543-50). Of note, however, one study reported that this alteration did not significantly impact the expression of transcripts skipping CDS11 (exon 12) in RNA studies, and was shown to have reduced complementation of Brca2 loss and homology directed repair activity in mESC--based functional assays (Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because this variant has been identified in one or more patients with Fanconi Anemia, this alteration may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		3.9
Vest4		0.88
GERP RS		2.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs876661261; hg19: chr13-32918712;