rs80359682

Positions:

• chr13-32357913-AAAG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_000059.4(BRCA2):​c.7795_7797del​(p.Glu2599del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:4
• Conservation: PhyloP100: 8.68

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000059.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 13-32357913-AAAG-A is Pathogenic according to our data. Variant chr13-32357913-AAAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52409.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=4, Pathogenic=1}. Variant chr13-32357913-AAAG-A is described in Lovd as [Pathogenic]. Variant chr13-32357913-AAAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7795_7797del	p.Glu2599del	inframe_deletion	16/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7795_7797del	p.Glu2599del	inframe_deletion	16/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461724 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	a heterozygous in-frame deletion in the BRCA2 gene was detected. This in-frame deletion of three nucleotides in BRCA2 is denoted c.7795_7797delGAA at the cDNA level and p.Glu2598del (E2598del) at the protein level. The This deletion of a single Glutamic Acid residue occurs at a position that is conserved across species and is located in the DNA binding domain (Yang 2002). This variant has been reported in several individuals evaluated for Hereditary Breast and Ovarian Cancer (Coulet 2010, Caux-Moncoutier 2011, Lecarpentier 2012, Castera 2014, Radrigeuz-Balada 2016). Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA2 Glu2598del to be a Variant of Uncertain Significance. This mutation has 5 entries in ClinVar. One entry is listed as pathogenic, one entry is listed as likely pathogenic, 3 entries are listed as variant of unknown significance. This mutation is not listed in the ExAC database. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 15, 2022	This variant causes an in-frame deletion of a highly conserved glutamic acid at codon 2599 in the BRCA2 protein (PMID: 15060014). To our knowledge, functional assays have not been performed for this variant. This variant has been detected in two individuals affected with ovarian, fallopian tube or peritoneal cancer (PMID: 29084914, 29240602) and over 100 families suspected to be affected with hereditary breast and ovarian cancer (PMID: 21120943, 24549055, 27886673, 34597585) with a family history likelihood ratio for pathogenicity of 229.56 (PMID: 34597585). This variant is estimated to co-segregate with disease with likelihood ratios for causality of greater than 310,000 from 87 individual carriers analyzed (ClinVar variation ID 52409) and 10,545,472 from 14 families analyzed (PMID: 34597585), respectively. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 16, 2024	The c.7795_7797delGAA variant (also known as p.E2599del) is located in coding exon 15 of the BRCA2 gene. This variant results from an in-frame GAA deletion at nucleotide positions 7795 to 7797. This results in the in-frame deletion of a glutamic acid at codon 2599. This amino acid position is highly conserved in available vertebrate species. This alteration has been detected in individuals from breast and/or ovarian cancer cohorts (Houdayer C et al. Hum. Mutat., 2012 Aug;33:1228-38; Rodríguez-Balada M et al. Cancer Genet, 2016 Nov;209:487-492; Labidi-Galy SI et al. Clin. Cancer Res., 2018 Jan;24:326-333; Caux-Moncoutier V et al. Hum. Mutat., 2011 Mar;32:325-34). In a large, worldwide study of BRCA1/2 mutation positive families, this variant was identified in a total of 12 French families (Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). This alteration was also classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, and tumor pathology data, including strong co-segregation data from 14 families with this variant (Caputo SM et al. Am J Hum Genet. 2021 Oct;108(10):1907-1923). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2023	This variant, c.7795_7797del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Glu2599del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 20858050, 21120943, 24549055, 29240602). ClinVar contains an entry for this variant (Variation ID: 52409). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Aug 13, 2020	Data included in classification: This variant is absent from population database gnomAD (PM2_mod) and has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 20858050, 21120943, 24549055 and 29240602) (PS4_mod). This variant is predicted to result in the deletion of 1 amino acid residue from the BRCA2 protein (p.Glu2599del) (PM4_sup). The deletion is within the BRCA2 binding domain (AA 2481-3156) a hotspot region as defined by the ENIGMA BRCA1/2 gene variant classification criteria (2017). Data not included in classification: Personal communication with French laboratories revealed the variant to be a well-known BRCA2 mutation, particularly in Northern France. Co-segregation analyses by French laboratories lead to a LR causality >310000 and to a posterior probability of 0.9999992447747283. This result has not been published (reported in ClinVar as pathogenic in 2005). Additional communication revealed the variant to have been observed in 87 French families but there is no information on population size. Rebbeck et al., 2018 (PMID:29446198) indicate that the variant is predicted to be associated with stable mutant proteins (BS3_sup). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2017

This in-frame deletion of three nucleotides in BRCA2 is denoted c.7795_7797delGAA at the cDNA level and p.Glu2599del (E2599del) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 8023_8025delGAA. The normal sequence, with the bases that are deleted in brackets, is AGAA[delGAA]TTTTA. This deletion of a single Glutamic Acid residue occurs at a position that is conserved across species and is located in the DNA binding domain (Yang 2002). This variant has been reported in several individuals evaluated for Hereditary Breast and Ovarian Cancer (Coulet 2010, Caux-Moncoutier 2011, Lecarpentier 2012, Castera 2014, Radrigeuz-Balada 2016). Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA2 Glu2599del to be a variant of uncertain significance. -

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: rs80359682; hg19: chr13-32932050;