rs80359003

chr13-32357881-G-Achr13-32357881-G-T

Variant summary

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

The NM_000059.4(BRCA2):c.7757G>A(p.Trp2586Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000109 in 1,461,814 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: 0.000011 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 4.17

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 13-32357881-G-A is Pathogenic according to our data. Variant chr13-32357881-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 52401.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357881-G-A is described in Lovd as [Pathogenic]. Variant chr13-32357881-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7757G>A	p.Trp2586Ter	stop_gained	16/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7757G>A	p.Trp2586Ter	stop_gained	16/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251434 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

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: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461814 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727206

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: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000492 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6

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	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jun 05, 2020	The BRCA2 c.7757G>A variant is classified as Pathogenic (PVS1, PM2, PP5) The BRCA2 c.7757G>A variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 2586. The variant is rare in population databases (gnomAD allele frequency = 0.00081% (PM2). The variant has been reported in dbSNP (rs80359003) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 52401). -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Trp2586X variant has been reported in 8/4826 proband chromosomes (frequency 0.002) of individuals with breast and/or ovarian cancer increasing the likelihood this variant is pathogenic, however, no normal population controls were included in these studies (Alsop 2012, Callahan 2007, Jonsson 2005, Meindl 2002, Perkowska 2003, Watson 2009, Weitzel 2005) It is reported in the BIC (x5) database as clinically significant. The variant leads to a premature stop codon at position 2586 which is predicted to cause premature truncation or an absent protein product and loss of function. Loss of function of the BRCA2 gene is an established disease mechanism for hereditary breast cancer. This variant is classified as pathogenic -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 11, 2013	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 30, 2021	Variant summary: BRCA2 c.7757G>A (p.Trp2586X) 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 8e-06 in 251434 control chromosomes. c.7757G>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, an expert panel (ENIGMA) and a large consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. 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	Invitae	Jan 09, 2024	This sequence change creates a premature translational stop signal (p.Trp2586*) 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 (rs80359003, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer and prostate cancer (PMID: 11802209, 12673801, 16528604, 23035815, 23569316, 23633455, 25485004). ClinVar contains an entry for this variant (Variation ID: 52401). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Trp2586X variant in BRCA2 has been reported in at least 14 individuals with BRCA2-related cancer (Perkowska 2003, Willems-Jones 2012, George 2013, Li 2018, BIC database). It has also been identified in 2/113726 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant leads to a premature termination codon at position 2586, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Another variant, c.7758G>A, resulting in the same amino acid change has been identified in individuals with BRCA2-related cancers and is classified as pathogenic by this laboratory. Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 52401). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PS1. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 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; Observed in individuals with personal or family history of BRCA2-related cancers (Perkowska et al., 2003; Jonsson et al., 2005; George et al., 2013; Walker et al., 2014; Murali et al., 2021; Evans et al., 2022); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 7985G>A; This variant is associated with the following publications: (PMID: 25628955, 25371446, 26833046, 28127413, 11802209, 19620486, 34657373, 29922827, 28888541, 23633455, 12673801, 23035815, 24333842, 16140926, 16528604, 27225637, 25485004, 12442275, 22655046, 25716084, 23233716, 27836010, 19899408, 17761984, 22711857, 29752822, 29446198, 30720243, 25525159, 31825140, 30787465, 33087929, 23524863, 20104584, 23569316, 33113089, 34399810, 33471991, 33758026) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 15, 2021	The p.W2586* pathogenic mutation (also known as c.7757G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7757. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This alteration has been reported in multiple breast and/or ovarian cancer families (Perkowska M et al. Hum. Mutat., 2003 May;21:553-4; Jönsson G et al. Cancer Res., 2005 Sep;65:7612-21; Alsop K et al. J Clin Oncol, 2012 Jul;30:2654-63; Conner JR et al. Gynecol. Oncol., 2014 Feb;132:280-6; Walker R et al. Can Urol Assoc J, 2014 Nov;8:E783-8; Li JY et al. Int J Cancer, 2019 01;144:281-289; Petridis C et al. Cancer Epidemiol Biomarkers Prev, 2019 07;28:1162-1168; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in individuals diagnosed with prostate cancer (Willems-Jones A et al. BJU Int. 2012 Dec;110(11 Pt C):E1181-6; Sandhu SK et al. Ann Oncol, 2013 May;24:1416-8; Walker R et al. Can Urol Assoc J 2014 Nov; 8(11-12):E783-8). This mutation has been identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 7985G>A in published literature. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	This variant changes 1 nucleotide in exon 16 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 reported in several individuals affected with breast and/or ovarian cancer (PMID: 12673801, 22711857, 23633455, 24333842, 33113089, 33471991, Color internal data). This variant has been identified in families with suspected hereditary breast and ovarian cancer syndrome, including 21 families among the CIMBA participants (PMID: 11802209, 16528604, 29446198). This variant has been identified in 2/251434 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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Jul 13, 2015

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A;A
Vest4		0.95
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80359003; hg19: chr13-32932018;