rs80359557

chr13-32340432-CAA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):c.6078_6079del(p.Glu2028ArgfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T2026T) 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: 0.810

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32340432-CAA-C is Pathogenic according to our data. Variant chr13-32340432-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 52003.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340432-CAA-C is described in Lovd as [Pathogenic]. Variant chr13-32340432-CAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6078_6079del	p.Glu2028ArgfsTer20	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6078_6079del	p.Glu2028ArgfsTer20	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

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

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:4

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)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 13, 2023	The BRCA2 c.6078_6079del (p.Glu2028ArgfsTer20) variant, also referred to as c.6306delAA, causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. The p.Glu2028ArgfsTer20 variant has been identified in three families with a history of cancer; however, phenotype details were unavailable (PMID: 15131399). Additionally, this variant was identified in two individuals with a history of breast cancer (PMID: 34284872). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as pathogenic by a ClinVar expert panel. Based on the available evidence, the c.6078_6079del (p.Glu2028ArgfsTer20) variant is classified as pathogenic for hereditary breast and ovarian cancer. -
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 breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2017	Variant summary: The BRCA2 c.6078_6079delAA (p.Glu2028Argfs) variant, alternatively also known as 6306delAA and/or 6306_6307delAA, results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay (NMD), which is commonly known mechanisms for disease. If NMD is escaped this variant is expected to truncate multiple functional regions and domains) (one BRCA2 repeat, helical domain, oligonucleotide/oligosaccharide-binding 1 region, OB-folds, and Tower domain; via InterPro). Truncations downstream of this position have been classified as pathogenic by our laboratory and others (e.g. c.6270_6271delTA, c.6275_6276delTT, c.6333_6337delGAGAA, etc.). This variant is absent in 120736 control chromosomes from ExAC. In a publication, this variant has been reported in three HBOC families without phenotypic and genotypic details in family members (Lubinski_2004). In ClinVar, this variant has been reported in four patients with breast and/or ovarian cancer by clinical laboratories (BIC and Invitae). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 31, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52003). This variant is also known as 6306delAA. This premature translational stop signal has been observed in individual(s) with a personal and/or family history of BRCA2-related cancers (PMID: 15131399). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu2028Argfs*20) 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). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 03, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.6078_6079delAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 6078 to 6079, causing a translational frameshift with a predicted alternate stop codon (p.E2028Rfs*20). This pathogenic mutation, located in the ovarian cancer cluster region of the BRCA2 gene, has been reported in multiple families with breast and/or ovarian cancer (Lubinski J et al.Fam. Cancer 2004; 3(1):1-10). This variant is also designated as 6306delAA. 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 19, 2023

- -

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: rs80359557; hg19: chr13-32914569;