VCV000052826.83 - ClinVar

NM_000059.4(BRCA2):c.9382C>T (p.Arg3128Ter)

Germline

Top reviewed classifications are shown here.

Submission summary:

51 submissions

50 submitters

11 conditions

Reviewed by expert panel

Pathogenic

Apr 2016 by Evidence-based…

for Breast-ovarian cancer, familial, susceptibility to, 2

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.9382C>T (p.Arg3128Ter)

Variation ID: 52826 Accession: VCV000052826.83

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32394814 (GRCh38) [ NCBI UCSC ] 13: 32968951 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 1, 2014	Nov 17, 2024	Apr 22, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.9382C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Arg3128Ter	nonsense
NC_000013.11:g.32394814C>T
NC_000013.10:g.32968951C>T
NG_012772.3:g.84335C>T
LRG_293:g.84335C>T
LRG_293t1:c.9382C>T	LRG_293p1:p.Arg3128Ter
U43746.1:n.9610C>T

... more HGVS ... less HGVS

Protein change

R3128*

Other names

p.R3128*:CGA>TGA
9610C>T

Canonical SPDI

NC_000013.11:32394813:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

protein truncation; Variation Ontology [ VariO:0015]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

Links

ClinGen: CA026127 dbSNP: rs80359212 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	-	-

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary breast ovarian cancer syndrome	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Jan 25, 2024	RCV000045807.31
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (20)	reviewed by expert panel	Apr 22, 2016	RCV000077469.32
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000160169.32
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 11, 2023	RCV000131048.20
Breast neoplasm	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Nov 1, 2015	RCV000240732.11
Familial cancer of breast	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 21, 2024	RCV000474912.12
Breast-ovarian cancer, familial, susceptibility to, 2 Familial cancer of breast Fanconi anemia complementation group D1 Glioma susceptibility 3 Malignant tumor of prostate Medulloblastoma Pancreatic cancer, susceptibility to, 2 Wilms tumor 1	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763332.10
Breast and/or ovarian cancer	Pathogenic (3)	criteria provided, single submitter	Aug 16, 2019	RCV000735625.13
BRCA2-related disorder	Pathogenic (2)	criteria provided, single submitter	Mar 5, 2022	RCV001849300.13
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003162394.8
NICE approved PARP inhibitor treatment	Pathogenic (1)	criteria provided, single submitter	Nov 11, 2024	RCV004782034.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 22, 2016)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015)) Method: curation	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Accession: SCV000282472.1 First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016	Comment: Variant allele predicted to encode a truncated non-functional protein.
Pathogenic (Nov 01, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Breast neoplasm Affected status: yes Allele origin: germline	Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University Additional submitter: Asia and Emerging Markets iMed, AstraZeneca Accession: SCV000265916.1 First in ClinVar: Sep 14, 2016 Last updated: Sep 14, 2016	Publications: PubMed (1) PubMed: 27257965 Number of individuals with the variant: 1 Geographic origin: China
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Genologica Medica Additional submitter: Servicio Andaluz de Salud, Hospital Universitario Virgen de la Victoria Accession: SCV000577977.1 First in ClinVar: Nov 05, 2016 Last updated: Nov 05, 2016	Family history: yes Ethnicity/Population group: Causasians Geographic origin: Spain Tissue: Blood Secondary finding: no
Pathogenic (Apr 20, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Department of Pathology and Molecular Medicine, Queen's University Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000588129.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017
Pathogenic (Apr 15, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000202307.7 First in ClinVar: Jan 29, 2015 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 10978364‚ 20736950 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2 http://www.umd.be/BRCA2/ http://www.umd.be/BRCA2/ Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Oct 04, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary Breast and Ovarian Cancer Syndrome Affected status: no Allele origin: germline	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center Accession: SCV001424028.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020	Publications: PubMed (7) PubMed: 29446198‚ 28294317‚ 27741520‚ 28477318‚ 24916970‚ 10978364‚ 15168169 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (Mar 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: CSER-SouthSeq Accession: SCV001736883.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Comment: ACMG codes:PVS1; PS4; PM2; PP5 Number of individuals with the variant: 1 Clinical Features: Cryptorchidism (present) , Narrow mouth (present) , High palate (present) , Macrocephaly (present) , Abnormality of the face (present) , Posteriorly rotated ears (present) , … (more) Cryptorchidism (present) , Narrow mouth (present) , High palate (present) , Macrocephaly (present) , Abnormality of the face (present) , Posteriorly rotated ears (present) , Wide nose (present) , Downslanted palpebral fissures (present) , Ptosis (present) , Hypotonia (present) , Flexion contracture (present) , Bilateral ptosis (present) , Fetal growth restriction (present) , Small for gestational age (present) , Patent ductus arteriosus (present) , Clubfoot (present) , Arthrogryposis multiplex congenita (present) , Prominent forehead (present) (less)
Pathogenic (Aug 16, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Study: Canadian Open Genetics Repository Accession: SCV000902219.2 First in ClinVar: May 06, 2019 Last updated: Jan 03, 2022
Pathogenic (Apr 30, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002067384.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: 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 … (more) 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). (less)
Pathogenic (Nov 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Genetics Program, Instituto Nacional de Cancer Accession: SCV002515164.1 First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022	Publications: PubMed (1) PubMed: 36329109 Geographic origin: Brazil
Pathogenic (Jul 01, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Department of Medical Genetics, Oslo University Hospital Accession: SCV000605659.3 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022	Number of individuals with the variant: 1
Pathogenic (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Hereditary breast and ovarian cancer syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000838903.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (Oct 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024756.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (May 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Accession: SCV005045926.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Comment: PVS1; PM5_PTC_Strong
Pathogenic (Mar 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000540993.2 First in ClinVar: Apr 17, 2017 Last updated: Jun 17, 2024
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV005090075.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024
Pathogenic (Apr 21, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Michigan Medical Genetics Laboratories, University of Michigan Accession: SCV000267830.1 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015	Tissue: Blood
Pathogenic (-)	criteria provided, single submitter (Silva et al. (BMC Med Genet. 2014)) Method: research	Breast Cancer Affected status: yes Allele origin: germline	A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center Accession: SCV000492448.1 First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017	Publications: PubMed (2) PubMed: 23469205‚ 24884479
Pathogenic (Jul 19, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Bioinformatics dept., Datar Cancer Genetics Limited, India Accession: SCV000584011.1 First in ClinVar: Nov 05, 2016 Last updated: Nov 05, 2016	Publications: PubMed (1) PubMed: 10978364 Age: 30-39 years Sex: female Ethnicity/Population group: South Asian Geographic origin: India
Pathogenic (Aug 14, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695236.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (11) PubMed: 17925560‚ 16905680‚ 24156927‚ 19491284‚ 18465347‚ 10978364‚ 23096105‚ 19016756‚ 15168169‚ 20104584‚ 11400546 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 08, 2014)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743366.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Sep 21, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744563.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Feb 06, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000839931.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: 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 … (more) 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. (less)
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Medulloblastoma Familial prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894009.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Mar 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	BRCA2-related disorder Affected status: yes Allele origin: germline	DASA Accession: SCV002107122.2 First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022	Publications: PubMed (5) PubMed: 10978364‚ 16683254‚ 24916970‚ 15168169‚ 16905680 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1 Sex: male Geographic origin: Brazil
Pathogenic (Oct 02, 2015)	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge Accession: SCV000328122.4 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022
Pathogenic (Jul 28, 2015)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000677708.2 First in ClinVar: Nov 05, 2016 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 20736950‚ 10978364‚ 24556621‚ 15168169‚ 16905680
Pathogenic (Sep 04, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000210506.16 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Oct 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004100711.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Comment: Criteria applied: PVS1,PM5_STR Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Oct 25, 2019)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000296605.5 First in ClinVar: Jun 24, 2016 Last updated: Jan 06, 2024	Publications: PubMed (7) PubMed: 26295337‚ 10978364‚ 20736950‚ 24556621‚ 16905680‚ 29088781‚ 25428789 Comment: 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 … (more) 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. (less)
Pathogenic (Jan 25, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000073820.14 First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024	Publications: PubMed (12) PubMed: 28492532‚ 20104584‚ 10978364‚ 11400546‚ 15168169‚ 16683254‚ 16905680‚ 20736950‚ 24156927‚ 24556621‚ 24728189‚ 24916970 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000684059.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (11) PubMed: 10978364‚ 11400546‚ 16905680‚ 17925560‚ 24728189‚ 25452441‚ 28294317‚ 28477318‚ 29088781‚ 29339979‚ 29907814 Comment: 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 … (more) 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. (less)
Pathogenic (May 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004846164.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (10) PubMed: 8988179‚ 11897832‚ 25476495‚ 29088781‚ 29371908‚ 29446198‚ 31325073‚ 32438681‚ 34567246‚ 36232564 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 1
Pathogenic (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848528.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (9) PubMed: 24556621‚ 16683254‚ 24156927‚ 28477318‚ 29088781‚ 20736950‚ 24728189‚ 10978364‚ 27741520 Comment: 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, … (more) 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. (less)
Pathogenic (Dec 16, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000185978.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (11) PubMed: 10978364‚ 20736950‚ 24884479‚ 24916970‚ 26287763‚ 27257965‚ 27469594‚ 27741520‚ 29088781‚ 29371908‚ 34567246 Comment: 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 … (more) 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. (less)
Pathogenic (May 21, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004100699.2 First in ClinVar: Nov 04, 2023 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PM5_STR Clinical Features: Family history of cancer (present) Sex: male
Pathogenic (Nov 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NICE approved PARP inhibitor treatment Affected status: yes Allele origin: germline	NHS Central & South Genomic Laboratory Hub Accession: SCV005393987.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024
Pathogenic (May 29, 2002)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000147627.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Observation 1: Number of individuals with the variant: 10 Observation 2: Number of individuals with the variant: 1 Geographic origin: African American Observation 3: Number of individuals with the variant: 2 Geographic origin: Western European Observation 4: Number of individuals with the variant: 2 Ethnicity/Population group: African Observation 5: Number of individuals with the variant: 1 Ethnicity/Population group: African American, Latin American, Caribbean Observation 6: Number of individuals with the variant: 1 Ethnicity/Population group: Ashkenazi Observation 7: Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Geographic origin: English Observation 8: Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Geographic origin: Germany Observation 9: Number of individuals with the variant: 2 Ethnicity/Population group: Central/Eastern European Observation 10: Number of individuals with the variant: 1 Ethnicity/Population group: French Canadian Observation 11: Number of individuals with the variant: 1 Ethnicity/Population group: Galician Geographic origin: Spain Observation 12: Number of individuals with the variant: 1 Ethnicity/Population group: Indian Observation 13: Number of individuals with the variant: 5 Ethnicity/Population group: Latin American, Caribbean Observation 14: Number of individuals with the variant: 1 Ethnicity/Population group: Near Eastern Observation 15: Number of individuals with the variant: 1 Ethnicity/Population group: Near Eastern Mid Eastern Latin American, Caribb Observation 16: Number of individuals with the variant: 17 Ethnicity/Population group: Western European Observation 17: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, French Observation 18: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, Italian English
Pathogenic (Jan 23, 2013)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: not provided Allele origin: germline	Sharing Clinical Reports Project (SCRP) Accession: SCV000109267.5 First in ClinVar: Dec 23, 2013 Last updated: Jun 24, 2016
Pathogenic (Jan 31, 2014)	no assertion criteria provided Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000588001.1 First in ClinVar: Apr 16, 2017 Last updated: Apr 16, 2017
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733337.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958914.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Mar 07, 2024)	no assertion criteria provided Method: clinical testing	BRCA2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005360834.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The BRCA2 c.9382C>T variant is predicted to result in premature protein termination (p.Arg3128). This variant has been reported in multiple individuals affected with breast, ovarian … (more) The BRCA2 c.9382C>T variant is predicted to result in premature protein termination (p.Arg3128). This variant has been reported in multiple individuals affected with breast, ovarian and prostate cancer (Edwards et al. 2010. PubMed ID: 20736950; Leongamornlert et al. 2014. PubMed ID: 24556621; Natarajan et al. 2016. PubMed ID: 27831900; Sun et al. 2017. PubMed ID: 28724667; Gabaldó Barrios. 2017. PubMed ID: 28477318). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD. Nonsense variants in BRCA2 are expected to be pathogenic, and this variant has been classified as pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52826). Given the evidence, we interpret c.9382C>T (p.Arg3128*) as pathogenic. (less)
Pathogenic (Feb 11, 2015)	no assertion criteria provided (clinical testing) Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Institute of Human Genetics, Medical University Innsbruck Study: BRCA-Tyrol Accession: SCV000212034.1 First in ClinVar: Mar 03, 2015 Last updated: Mar 03, 2015 Comment: BRCA-mutation spectrum Western Austria
Pathogenic (Jul 17, 2008)	no assertion criteria provided Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000863763.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018
Pathogenic (Jun 11, 2019)	no assertion criteria provided Method: clinical testing	Breast and/or ovarian cancer Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV001451892.1 First in ClinVar: Dec 26, 2020 Last updated: Dec 26, 2020	Publications: PubMed (1) PubMed: 32295079 Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000592281.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021	Comment: 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 … (more) 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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less)
Pathogenic (Jul 01, 2021)	no assertion criteria provided Method: research	Gastric cancer Affected status: unknown Allele origin: germline	Laboratory for Genotyping Development, RIKEN Accession: SCV002758143.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593
Pathogenic (Mar 02, 2020)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV004243871.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Pathogenic (May 24, 2021)	no assertion criteria provided Method: case-control	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) Accession: SCV005061349.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Publications: PubMed (1) PubMed: 38922859 Secondary finding: no
not provided (-)	no classification provided Method: phenotyping only	Hereditary breast and ovarian cancer syndrome Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000840274.1 First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018	Comment: 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 … (more) 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. (less) Clinical Features: Myopia (present) Age: 60-69 years Sex: female Method: Variant reported as confirmed, but method not specified. Testing laboratory: Color Health, Inc Date variant was reported to submitter: 2017-12-22 Testing laboratory interpretation: Pathogenic
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Comment:

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.

Comment:

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).

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

The BRCA2 c.9382C>T variant is predicted to result in premature protein termination (p.Arg3128*). This variant has been reported in multiple individuals affected with breast, ovarian and prostate cancer (Edwards et al. 2010. PubMed ID: 20736950; Leongamornlert et al. 2014. PubMed ID: 24556621; Natarajan et al. 2016. PubMed ID: 27831900; Sun et al. 2017. PubMed ID: 28724667; Gabaldó Barrios. 2017. PubMed ID: 28477318). This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD. Nonsense variants in BRCA2 are expected to be pathogenic, and this variant has been classified as pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52826). Given the evidence, we interpret c.9382C>T (p.Arg3128*) as pathogenic.

Comment:

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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
protein truncation (VariO:0015)			Bioinformatics dept., Datar Cancer Genetics Limited, India Accession: SCV000584011.1	Publications PubMed (1)

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Featuring BRCA1 and BRCA2 germline mutational landscape from Asturias (North Spain).	Pitiot AS	Clinical genetics	2024	PMID: 38922859
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.	Usui Y	The New England journal of medicine	2023	PMID: 36988593
Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service.	Matta BP	Scientific reports	2022	PMID: 36329109
Germline Variants in 32 Cancer-Related Genes among 700 Chinese Breast Cancer Patients by Next-Generation Sequencing: A Clinic-Based, Observational Study.	Yang L	International journal of molecular sciences	2022	PMID: 36232564
Hereditary breast cancer and ancestry in the Madeira archipelago: an exploratory study.	Miguel I	Ecancermedicalscience	2021	PMID: 34567246
Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome.	Santonocito C	Cancers	2020	PMID: 32438681
Assessing the effectiveness of the National Comprehensive Cancer Network genetic testing guidelines in identifying African American breast cancer patients with deleterious genetic mutations.	Ademuyiwa FO	Breast cancer research and treatment	2019	PMID: 31325073
The germline mutational landscape of BRCA1 and BRCA2 in Brazil.	Palmero EI	Scientific reports	2018	PMID: 29907814
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.	Rebbeck TR	Human mutation	2018	PMID: 29446198
Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds.	Dominguez-Valentin M	Hereditary cancer in clinical practice	2018	PMID: 29371908
BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway.	Heramb C	Hereditary cancer in clinical practice	2018	PMID: 29339979
BRCA1 and BRCA2 founder mutations account for 78% of germline carriers among hereditary breast cancer families in Chile.	Alvarez C	Oncotarget	2017	PMID: 29088781
Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers.	Gabaldó Barrios X	Familial cancer	2017	PMID: 28477318
The spectrum of BRCA mutations and characteristics of BRCA-associated breast cancers in China: Screening of 2,991 patients and 1,043 controls by next-generation sequencing.	Lang GT	International journal of cancer	2017	PMID: 28294317
Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry.	Fernandes GC	Oncotarget	2016	PMID: 27741520
A Survey of BRCA1, BRCA2, and PALB2 mutations in women with breast cancer in Trinidad and Tobago.	Donenberg T	Breast cancer research and treatment	2016	PMID: 27469594
Prevalence and Prognostic Role of BRCA1/2 Variants in Unselected Chinese Breast Cancer Patients.	Zhong X	PloS one	2016	PMID: 27257965
A high frequency of BRCA mutations in young black women with breast cancer residing in Florida.	Pal T	Cancer	2015	PMID: 26287763
Incidence of BRCA1 and BRCA2 non-founder mutations in patients of Ashkenazi Jewish ancestry.	Rosenthal E	Breast cancer research and treatment	2015	PMID: 25476495
Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.	Couch FJ	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2015	PMID: 25452441
Inherited predisposition to breast cancer among African American women.	Churpek JE	Breast cancer research and treatment	2015	PMID: 25428789
The role of targeted BRCA1/BRCA2 mutation analysis in hereditary breast/ovarian cancer families of Portuguese ancestry.	Peixoto A	Clinical genetics	2015	PMID: 24916970
Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients.	Silva FC	BMC medical genetics	2014	PMID: 24884479
The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population.	Song H	Human molecular genetics	2014	PMID: 24728189
Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease.	Leongamornlert D	British journal of cancer	2014	PMID: 24556621
Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer.	Tea MK	Maturitas	2014	PMID: 24156927
Identification of a novel in-frame deletion in BRCA2 and analysis of variants of BRCA1/2 in Italian patients affected with hereditary breast and ovarian cancer.	Vietri MT	Clinical chemistry and laboratory medicine	2012	PMID: 23096105
Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis.	Edwards SM	British journal of cancer	2010	PMID: 20736950
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.	Borg A	Human mutation	2010	PMID: 20104584
Breast cancer in young women (YBC): prevalence of BRCA1/2 mutations and risk of secondary malignancies across diverse racial groups.	Haffty BG	Annals of oncology : official journal of the European Society for Medical Oncology	2009	PMID: 19491284
Cross-sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer.	Sugano K	Cancer science	2008	PMID: 19016756
BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer.	Thomassen M	Acta oncologica (Stockholm, Sweden)	2008	PMID: 18465347
BRCA1 and BRCA2 genetic testing in Hispanic patients: mutation prevalence and evaluation of the BRCAPRO risk assessment model.	Vogel KJ	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2007	PMID: 17925560
Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer.	Simard J	Journal of medical genetics	2007	PMID: 16905680
A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting.	van der Hout AH	Human mutation	2006	PMID: 16683254
Identification and evaluation of 55 genetic variations in the BRCA1 and the BRCA2 genes of patients from 50 Japanese breast cancer families.	Kawahara M	Journal of human genetics	2004	PMID: 15168169
Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany.	Hamann U	Journal of medical genetics	2002	PMID: 11897832
BRCA1/2 mutations in Swiss patients with familial or early-onset breast and ovarian cancer.	Schoumacher F	Swiss medical weekly	2001	PMID: 11400546
BRCA2 germline mutations among early onset breast cancer patients unselected for family history of the disease.	Plaschke J	Journal of medical genetics	2000	PMID: 10978364
Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene.	Gayther SA	Nature genetics	1997	PMID: 8988179
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2	-	-	-	-
http://www.umd.be/BRCA2/	-	-	-	-
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Text-mined citations for rs80359212 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.9382C>T (p.Arg3128Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80359212 ...