13-32394814-C-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.9382C>T(p.Arg3128Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,968 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. RP3128R?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:45 O:1
• Conservation: PhyloP100: 1.84

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 13-32394814-C-T is Pathogenic according to our data. Variant chr13-32394814-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 52826.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32394814-C-T is described in Lovd as [Pathogenic]. Variant chr13-32394814-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9382C>T	p.Arg3128Ter	stop_gained	25/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9382C>T	p.Arg3128Ter	stop_gained	25/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251360 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135856

Gnomad AFR exome AF: 0.000123

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 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: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000354 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:45 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:18

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)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 23, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Medical University Innsbruck	Feb 11, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 29, 2021	ACMG codes:PVS1; PS4; PM2; PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 31, 2023	The c.9382C>T (p.Arg3128*) variant in the BRCA2 gene is located on the exon 25 and introduce a premature translation termination codon (p.Arg3128*), resulting in an absent or disrupted protein product. The variant has been identified in multiple individuals with breast and/or ovarian cancer (PMID: 34567246, 29088781, 25476495, 36232564, 32438681, 29371908, 31325073). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 29446198, 11897832, 8988179). The variant is reported in ClinVar as pathogenic (ID: 52826) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (6/282750). Therefore, the c.9382C>T (p.Arg3128*) variant of BRCA2 has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Bioinformatics dept., Datar Cancer Genetics Limited, India	Jul 19, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 06, 2018	This c.9382C>T (p.R3128*) missense variant is predicted to result in a premature stop codon and has been reported in multiple individuals with breast, ovarian, and prostate cancer (PMID: 10978364, 24156927, 16683254, 24916970, 15168169, 11400546, 16905680, 24728189, 24556621, 20736950). Therefore, the c.9382C>T (p.R3128*) variant in the BRCA2 gene is classified as pathogenic. -
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	Institute of Human Genetics, University of Leipzig Medical Center	Oct 16, 2023	Criteria applied: PVS1,PM5_STR -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 28, 2015	- -

Hereditary breast ovarian cancer syndrome Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Arg3128*) 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 (rs80359212, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and prostate cancer (PMID: 10978364, 11400546, 15168169, 16683254, 16905680, 20736950, 24156927, 24556621, 24728189, 24916970). This variant is also known as 9610C>T. ClinVar contains an entry for this variant (Variation ID: 52826). 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	Aug 14, 2017	Variant summary: The BRCA2 c.9382C>T (p.Arg3128X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g., c.9403delC [p.Leu3135fsX28], c.9435_9436delGT [p.Ser3147fsX2], and c.9672dupA [p.Tyr3225fsX30]). This variant was found in the large control database ExAC at a frequency of 0.0000165 (2/121360 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been reported in multiple affected individuals and was shown to segregate with the disease in multiple HBOC families. In addition, multiple clinical diagnostic laboratories/reputable databases 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	Mendelics	Jul 02, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Oct 04, 2018	This sequence variant is a single nucleotide substitution (C>T) in exon 25/28 of the BRCA2 gene that changes the arginine at position 3128 to an early termination codon. This is expected to result in nonsense-mediated decay of the resulting transcript and no functional protein from the variant allele. This is a rare variant, and is found at a frequency of 0.00002 in the gnomAD population database (5/277070 alleles, 0 homozygotes). This is a well-characterized, known pathogenic variant which has been reported in breast and ovarian cancer cohorts and families worldwide (PMIDs 29446198, 28294317, 27741520, 28477318, 24916970, 10978364, 15168169). This variant has been identified and classified by the ENIGMA BRCA1 and BRCA2 expert consortium as a pathogenic variant on April 22, 2016. Considering all of the available data, we consider this to be a pathogenic variant. -
Pathogenic, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 15, 2021	The p.Arg3128X variant in BRCA2 has been previously reported in >15 individuals with BRCA2-associated cancers (Plaschke 2000 PMID:10978364, Edwards 2010 PMID: 20736950, Leongamornlert 2014 PMID:24556621, Song 2014 PMID: 24728189, Fernandes 2016 PMID:27741520, Gabaldo Barrios 2017 PMID: 28477318, Alvarez 2017 PMID:29088781, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/, ClinVar Variation ID:52826). It has also been identified in 0.014% (6/41436) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense variant leads to a premature termination codon at position 3128, 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 individuals with HBOC. This variant was classified as pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282472.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_supporting, PVS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -

not provided Pathogenic:7

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	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 25, 2019	This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in families affected with breast, ovarian and/or prostate cancer in literature (PMID: 10978364 (2000), 16905680 (2007), 20736950 (2010), 24556621 (2014), 29088781 (2017)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Arg3128* variant leads to a premature stop codon at position 3128, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of disease for the BRCA2 gene. This variant has been previously reported in the literature in numerous publications in multiple individuals (>50) with breast, ovarian and prostate cancer and is recognized as a pathogenic variant (selected publications: Adams 2011, Vogel 2007, Sugano 2008, Edwards 2010). 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	Genetic Services Laboratory, University of Chicago	Apr 30, 2020	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.9382C>T, which results in the creation of a premature stop codon at amino acid position 3128, p.Arg3128*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA2 protein with potentially abnormal function. This pathogenic sequence change has previously been described in patients with a personal and/or family history of breast cancer, as well as patients with prostate cancer and ovarian cancer (PMIDs 10978364, 29088781, 29371908, 20736950, 24728189). The p.Arg3128* pathogenic sequence change is present in the heterozygous state in six individuals in the gnomAD population database (dbSNP rs80359212). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Plaschke 2000, Simard 2007, Vogel 2007, Sugano 2008, Edwards 2010, Leongamornlert 2014, Peixoto 2015, Rosenthal 2015, Kwong 2016); Not observed at a 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 9610C>T; This variant is associated with the following publications: (PMID: 19016756, 25980754, 11400546, 29884136, 28651617, 28477318, 28294317, 25525159, 10978364, 24556621, 20736950, 17925560, 16905680, 20104584, 24916970, 25850536, 24156927, 15168169, 24728189, 27157322, 27469594, 29371908, 29339979, 29433453, 28279176, 27831900, 29088781, 29907814, 28724667, 30720863, 29446198, 30720243, 30702160, 32467295, 33646313, 32318955, 31447099, 32853339, 31825140, 32338768, 30787465) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 05, 2022	- -

Breast and/or ovarian cancer Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 16, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 17, 2008	- -
Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Jun 11, 2019	- -

Breast neoplasm Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	Nov 01, 2015	- -
Pathogenic, criteria provided, single submitter	research	A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center	-	- -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 22, 2023	Criteria applied: PVS1,PS4,PM5_STR -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 11, 2023	This variant changes 1 nucleotide in exon 25 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 individuals affected with breast and/or ovarian cancer (PMID: 10978364, 11400546, 16905680, 17925560, 24728189, 25452441, 28294317, 28477318, 29088781, 29339979, 29907814). This variant has been identified in 6/282750 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	Dec 16, 2021	The p.R3128* pathogenic mutation (also known as c.9382C>T), located in coding exon 24 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9382. This changes the amino acid from an arginine to a stop codon within coding exon 24. This mutation has been observed in both early-onset breast cancer and early-onset prostate cancer cohorts, as well as in multiple families of various ethnicities with Hereditary Breast and Ovarian Cancer syndrome (Plaschke J et al. J. Med. Genet. 2000 Sep;37:E17; Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Pal T et al. Cancer. 2015 Dec;121:4173-80; Zhong X et al. PLoS ONE. 2016 Jun;11:e0156789; Donenberg T et al. Breast Cancer Res. Treat. 2016 Aug;159:131-8; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Alvarez C et al. Oncotarget. 2017 Sep;8:74233-74243). In addition to Portuguese and Brazilian populations, this mutation has been reported to be frequent in HBOC patients of Madeira ancestry (Silva FC et al. BMC Med Genet. 2014 May;15:55; Peixoto A et al. Clin Genet. 2015 Jul; 88(1):41-8; Miguel I. et al. Ecancermedicalscience. 2012 Jul;15:1261). While this mutation was reported in conjunction with another BRCA2 pathogenic mutation, authors do not comment on phase determination in this individual who was diagnosed with breast cancer at age 44 (Dominguez-Valentin M et al. Hered Cancer Clin Pract. 2018 Jan;16:4). Of note, this alteration is also designated as 9610C>T 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. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

BRCA2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 05, 2022

The c.9382C>T;p.(Arg3128*) variant creates a premature translational stop signal in the BRCA2 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 52826; PMID: 10978364; 16683254; 24916970; 15168169; 16905680) - PS4. The variant is present at low allele frequencies population databases (rs80359212 – gnomAD 0.0002122%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	45
Dann	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.80	D
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		5.0

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: rs80359212; hg19: chr13-32968951; COSMIC: COSV66461429; COSMIC: COSV66461429;