rs80359004

chr13-32357882-G-Achr13-32357882-G-Cchr13-32357882-G-T

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.7758G>A(p.Trp2586Ter) 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 (★★★). 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: 3.42

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 13-32357882-G-A is Pathogenic according to our data. Variant chr13-32357882-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38116.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357882-G-A is described in Lovd as [Pathogenic]. Variant chr13-32357882-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7758G>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.7758G>A	p.Trp2586Ter	stop_gained	16/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jun 09, 2008	- -
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	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Trp2586* variant was identified in 18 of 62552 proband chromosomes (frequency: 0.0003) from individuals or families with breast and ovarian cancer (Callahan 2007, George 2013, Meindl 2002, Nahleh 2014, Perkowska 2003, Sinilnikova 2006, Weitzel 2005, Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80359004) as "With Pathogenic allele", in ClinVar (classified 11x as Pathogenic by GeneDx, Ambry Genetics, SCRP and 8 other submitters), in Cosmic (identified once in squamous cell carcinoma from skin tissue and confirmed somatic status), in the LOVD 3.0 (8x pathogenic) and in the UMD-LSDB (1 record of causal biological significance) databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Trp2586* variant leads to a premature stop codon at position 2586, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 30, 2022	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP -
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: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	Invitae	Jan 06, 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast, prostate and ovarian cancer (PMID: 2673801, 11802209, 16140926, 23035815, 23633455, 26681682). This variant is also known as c.7986G>A. ClinVar contains an entry for this variant (Variation ID: 38116). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2016	Variant summary: The BRCA2 variant, c.7758G>A (p.Trp2586X) causes a nonsense mutation involving a conserved nucleotide resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Research Institute, Aichi Cancer Center	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 13, 2017	The p.Trp2586X variant in BRCA2 has been reported >5 individuals with BRCA2-asso ciated cancers (Meindl 2002, Callahan 2007, Conner 2014, Nahleh 2015, and Breast Cancer Information Core (BIC) database) and was absent from large population st udies. This nonsense variant leads to a premature termination codon at position 2586, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in heredi tary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel ( ClinVar SCV000301200.2). In summary, this variant meets criteria to be classifie d as pathogenic for HBOC in an autosomal dominant manner based upon absence in c ontrols and the predicted impact to the protein. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2019	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 in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as BRCA2 7986G>A using alternate nomenclature; This variant is associated with the following publications: (PMID: 25628955, 11802209, 17761984, 24333842, 16140926, 25525159, 25371446, 21702907, 26564481, 16528604, 29446198, 31447099) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 29, 2021	The p.W2586* pathogenic mutation (also known as c.7758G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7758. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This mutation has been reported in multiple breast and/or ovarian cancer patients and families (Meindl A et al. Int J Cancer, 2002 Feb;97:472-80; Perkowska M et al. Hum. Mutat., 2003 May;21:553-4; Weitzel JN et al. Cancer Epidemiol Biomarkers Prev, 2005 Jul;14:1666-71; Jönsson G et al. Cancer Res, 2005 Sep;65:7612-21; Sinilnikova OM et al. Fam Cancer, 2006;5:15-20; Callahan MJ et al. J Clin Oncol, 2007 Sep;25:3985-90; Watson P et al. J Clin Oncol, 2009 Aug;27:3894-900; George J et al. Clin Cancer Res, 2013 Jul;19:3474-84; Conner JR et al. Gynecol Oncol, 2014 Feb;132:280-6; Nahleh Z et al. Am J Cancer Res, 2015 Dec;5:466-71; Eccles DM et al. Ann Oncol, 2016 Mar;27:467-73; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Dorling et al. N Engl J Med. 2021 02;384:428-439), as well as at least one prostate cancer patient (Willems-Jones A et al. BJU Int, 2012 Dec;110:E1181-6). Of note, this mutation is also designated as 7986G>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	Mar 02, 2022	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 5 individuals affected with breast and/or ovarian cancer, including 1 male individual and 1 individual affected with both breast and ovarian cancer (PMID: 24333842, 25628955, 33471991; Leiden Open Variation Database DB-ID BRCA2_00326233918338, 34377931). This variant has not been identified 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. -

Malignant tumor of urinary bladder Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Urology, Hospital Clinic de Barcelona

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A
Vest4		0.95
GERP RS		4.3

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: rs80359004; hg19: chr13-32932019; COSMIC: COSV66462892;