rs80359046

chr13-32363269-T-Achr13-32363269-T-Cchr13-32363269-T-G

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.8067T>A(p.Cys2689Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. C2689C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 0.327

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 13-32363269-T-A is Pathogenic according to our data. Variant chr13-32363269-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 52493.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32363269-T-A is described in Lovd as [Pathogenic]. Variant chr13-32363269-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8067T>A	p.Cys2689Ter	stop_gained	18/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8067T>A	p.Cys2689Ter	stop_gained	18/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 09, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 15, 2022	Variant summary: BRCA2 c.8067T>A (p.Cys2689X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251244 control chromosomes. c.8067T>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 24, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52493). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast or ovarian cancer (PMID: 9167459, 10638982, 22009639, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys2689*) 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:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2016	This variant is denoted BRCA2 c.8067T>A at the cDNA level and p.Cys2689Ter (C2689X) at the protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGT>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Using alternate nomenclature, this variant would be defined as BRCA2 8295T>A and has been reported in multiple individuals with personal and family histories consistent with hereditary breast cancer (Breast Cancer Linkage Consortium 1997, Litton 2000, Peelen 2000, van der Hout 2006, Bayraktar 2012). We consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2023

The p.C2689* pathogenic mutation (also known as c.8067T>A), located in coding exon 17 of the BRCA2 gene, results from a T to A substitution at nucleotide position 8067. This changes the amino acid from a cysteine to a stop codon within coding exon 17. This variant has been reported in studies of patients with suspected hereditary breast and/or ovarian cancer and in a patient with Fanconi anemia (Stratton M et al. Lancet 1997 May; 349(9064):1505-10; Peelen T et al. Br. J. Cancer 2000 Jan; 82(1):151-6.;Litton JK et al. Cancer 2012 Jan; 118(2):321-5; Bayraktar S et al. Cancer 2012 Mar; 118(6):1515-22; Ameziane N et al. Anemia 2012; 2012:132856; Vos JR et al. Cancer Epidemiol. Biomarkers Prev. 2014 Nov; 23(11):2482-91). 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

Dec 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A
Vest4		0.81
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs80359046; hg19: chr13-32937406;