13-32357920-A-G

Variant names:

• chr13-32357920-A-G
• rs780715340
• NM_000059.4:c.7796A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2_Supporting PS3 PM3 PP3

This summary comes from the ClinGen Evidence Repository: The c.7796A>G variant in BRCA2 is a missense variant predicted to cause substitution of Glutamic Acid by Glycine at amino acid 2599 (p.(Glu2599Gly)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.36, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0.06 predicts no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779857, 39779848) (PS3 met). mRNA experimental analysis indicates no impact on splicing (PMID:24123850), but is not applied as strong evidence against pathogenicity since missense impact has not been excluded (BP7_Strong (RNA) not met). This variant has been detected in one individual with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least one clinical feature of FA (physical features AND pathology findings) and confirmed chromosome breakage are seen in this individual. This individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (BRCA2:c.1813dup) which was confirmed to be in trans. Total points equated to 2 (PM3 met; PMIDs: 34504103, 33984160). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3, PM3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA387746086/MONDO:0700269/097

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:3
• Conservation: PhyloP100: 8.68
• Publications: 9 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.7796A>G	p.Glu2599Gly	missense	Exon 16 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.7796A>G	p.Glu2599Gly	missense	Exon 16 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.7796A>G	p.Glu2599Gly	missense	Exon 16 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.7796A>G	p.Glu2599Gly	missense	Exon 16 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.7796A>G	p.Glu2599Gly	missense	Exon 16 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.7427A>G	p.Glu2476Gly	missense	Exon 16 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Oct 10, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E2599G variant (also known as c.7796A>G), located in coding exon 15 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7796. The glutamic acid at codon 2599 is replaced by glycine, an amino acid with similar properties. This alteration was identified in an individual with another BRCA2 pathogenic mutation that presented with severe intolerance to chemotherapy and had abnormal results in chromosomal breakage analysis, however the individual did not present with fully penetrant Fanconi anemia (Castells-Roca, L. et al. NPJ Breast Cancer 2021 Sep;7(1):117.). Protein functional studies have determined this variant to be deleterious (Castells-Roca, L. et al. NPJ Breast Cancer 2021 Sep;7(1):117; Richardson, ME et al. Am J Hum Genet 2021 03;108(3):458-468; Hu C et al. Am J Hum Genet. 2024 Mar;111(3):584-593). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because this variant is identified in one or more patients with Fanconi anemia it 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.

Mar 17, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamic acid with glycine at codon 2599 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown this variant results in loss of homology-directed DNA repair activity (PMID: 33609447). This variant has been reported in trans with a pathogenic frameshift variant in BRCA2 in an individual affected with early-onset breast cancer (PMID: 34504103). This individual was also diagnosed with Fanconi anemia by intermediate chromosome fragility, but lacked childhood-onset and congenital clinical features typical of classic Fanconi anemia (PMID: 34504103). A different variant affecting the same codon, c.7795_7797del (p.Glu2599del), is considered to be disease-causing (ClinVar variation ID: 52409), suggesting that Glu at this position is important for the protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

BRCA2-related cancer predisposition Pathogenic:1

May 23, 2025

ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.7796A>G variant in BRCA2 is a missense variant predicted to cause substitution of Glutamic Acid by Glycine at amino acid 2599 (p.(Glu2599Gly)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.36, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0.06 predicts no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779857, 39779848) (PS3 met). mRNA experimental analysis indicates no impact on splicing (PMID: 24123850), but is not applied as strong evidence against pathogenicity since missense impact has not been excluded (BP7_Strong (RNA) not met). This variant has been detected in one individual with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least one clinical feature of FA (physical features AND pathology findings) and confirmed chromosome breakage are seen in this individual. This individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant (BRCA2:c.1813dup) which was confirmed to be in trans. Total points equated to 2 (PM3 met; PMIDs: 34504103, 33984160). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3, PM3).

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Uncertain:1

May 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2599 of the BRCA2 protein (p.Glu2599Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34504103). ClinVar contains an entry for this variant (Variation ID: 483130). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 34504103). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.94	D
PhyloP100		8.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.81
MutPred		0.70		Loss of disorder (P = 0.1216)
MVP		0.98
MPC		0.17
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.76
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.020		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: rs780715340; hg19: chr13-32932057;