13-32333167-G-A

Position:

• chr13-32333167-G-A

Variant summary

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

The NM_000059.4(BRCA2):​c.1689G>A​(p.Trp563Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: -0.0280

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 13-32333167-G-A is Pathogenic according to our data. Variant chr13-32333167-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 51175.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32333167-G-A is described in Lovd as [Pathogenic]. Variant chr13-32333167-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1689G>A	p.Trp563Ter	stop_gained	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1689G>A	p.Trp563Ter	stop_gained	10/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251158 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461774 Hom.: 0 Cov.: 35 AF XY: 0.00000825 AC XY: 6 AN XY: 727178

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: 0.0000187

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4

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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
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	Counsyl	May 23, 2016	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2022	Variant summary: BRCA2 c.1689G>A (p.Trp563X) 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 allele was found at a frequency of 4e-06 in 251158 control chromosomes (gnomAD). c.1689G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Lubinski_2004,Hondow_2011, Meeks_2016). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change creates a premature translational stop signal (p.Trp563*) 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 present in population databases (rs80358456, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with cancer (PMID: 15131399). ClinVar contains an entry for this variant (Variation ID: 51175). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 15, 2019	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 1917G>A; This variant is associated with the following publications: (PMID: 18955455, 25525159, 20167696, 21702907, 28492532, 29202330, 15131399, 28726806, 30720243, 35578052, 31565484, 26586665, 29446198, 34161676, 20104584, 29262651, 29487695) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 01, 2022	This variant changes 1 nucleotide in exon 10 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in 6 individuals affected with breast cancer and 1 individual affected with ovarian cancer (PMID: 29262651, 33471991; Leiden Open Variation Database DB-ID BRCA2_001852). This variant has been identified in 1/251158 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 26, 2022	The p.W563* pathogenic mutation (also known as c.1689G>A), located in coding exon 9 of the BRCA2 gene, results from a G to A substitution at nucleotide position 1689. This changes the amino acid from a tryptophan to a stop codon within coding exon 9. 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. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Trp563X variant was identified in 1 of 880 proband chromosomes (frequency: 0.001) from individuals or families across several ethnicities with ovarian, male breast, pancreatic, prostate, colon, stomach and melanoma cancers (Lubinski 2004). The variant was also identified in ClinVar as pathogenic by Evidence-based Network for the interpretation of Germline Mutant Alleles, in Consortium of Investigators of Modifiers of BRCA1/2, in Invitae, in Breast Cancer Information Core, and in Research Molecular Genetics Laboratory, Women's College Hospital; and as likely pathogenic by Counsyl and Clinvitae. The variant was also identified 4X in LOVD 3.0 database with a frequency of 0.001, in BIC 6X as Class 5 with clinical importance, and in ARUP Laboratories databases 1X as definitely pathogenic . The variant was identified in dbSNP (ID:rs 80358456) as “with pathogenic allele”, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer databases or in the 1000 Genomes and the NHLBI GO sequencing projects. The variant was identified in control databases in 1 of 246026 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Finnish in 1 of 22280 chromosomes (freq: 0.00005), while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, and South Asian populations. The c.1689G>A variant leads to a premature stop codon at position 563 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Benign	0.97
Eigen	Benign	0.095
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.058	N
MutationTaster	Benign	1.0	A;A
Vest4		0.89
GERP RS		0.075

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80358456; hg19: chr13-32907304;