VCV000038208.78 - ClinVar

NM_000059.4(BRCA2):c.9097dup (p.Thr3033fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

43 submissions

42 submitters

14 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.9097dup (p.Thr3033fs)

Variation ID: 38208 Accession: VCV000038208.78

Type and length

Duplication, 1 bp

Location

Cytogenetic: 13q13.1 13: 32379885-32379886 (GRCh38) [ NCBI UCSC ] 13: 32954030 (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	Mar 29, 2015	Oct 13, 2024	Apr 22, 2016

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.9097dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Thr3033fs	frameshift
NM_000059.3:c.9090dupA
NM_000059.3:c.9097dupA
NC_000013.11:g.32379893dup
NC_000013.10:g.32954030dup
NG_012772.3:g.69414dup
LRG_293:g.69414dup

... more HGVS ... less HGVS

Protein change

T3033fs

Other names

9325_9326insA
p.Thr3033AsnfsX11
9325insA

Canonical SPDI

NC_000013.11:32379885:AAAAAAAA:AAAAAAAAA

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

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.

Links

ClinGen: CA025970 dbSNP: rs397507419 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	18969	19128

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.
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (9)	reviewed by expert panel	Apr 22, 2016	RCV000031791.26
not provided	Pathogenic (11)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000045711.40
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 28, 2023	RCV000130439.21
Hereditary breast ovarian cancer syndrome	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 5, 2023	RCV000195406.30
Breast-ovarian cancer, familial, susceptibility to, 1	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 26, 2024	RCV000210094.12
Familial cancer of breast	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Mar 22, 2024	RCV000585671.17
Breast and/or ovarian cancer	Pathogenic (3)	criteria provided, single submitter	Apr 28, 2023	RCV000735619.11
Ovarian neoplasm	Pathogenic (1)	no assertion criteria provided	Dec 1, 2018	RCV000785367.10
Malignant tumor of breast	Pathogenic (1)	no assertion criteria provided	-	RCV001353615.10
Breast carcinoma	Pathogenic (1)	no assertion criteria provided	Aug 8, 2021	RCV001554255.9
See cases	Pathogenic (1)	criteria provided, single submitter	Mar 31, 2023	RCV003334379.1
Malignant lymphoma, large B-cell, diffuse	Pathogenic (1)	no assertion criteria provided	Dec 4, 2023	RCV003448973.1
Breast-ovarian cancer, familial, susceptibility to, 2 Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	Oct 22, 2020	RCV002463351.8
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003162285.8
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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: SCV000282467.1 First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016	Comment: Variant allele predicted to encode a truncated non-functional protein.
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: SCV000196022.1 First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015	Tissue: Blood
Pathogenic (Dec 05, 2023)	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: SCV000073724.13 First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024	Publications: PubMed (6) PubMed: 28492532‚ 20104584‚ 9150172‚ 21138478‚ 22970155‚ 25940717 Comment: This sequence change creates a premature translational stop signal (p.Thr3033Asnfs11) 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.Thr3033Asnfs11) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer, pancreatic cancer, and Fanconi anemia (PMID: 9150172, 21138478, 22970155, 25940717). This variant is also known as c.9097_9098insA, 9325insA and 9317insA. ClinVar contains an entry for this variant (Variation ID: 38208). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 08, 2022)	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: SCV000185303.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 18489799 Comment: The c.9097dupA pathogenic mutation, located in coding exon 22 of the BRCA2 gene, results from a duplication of one nucleotide at position 9097, causing a … (more) The c.9097dupA pathogenic mutation, located in coding exon 22 of the BRCA2 gene, results from a duplication of one nucleotide at position 9097, causing a translational frameshift with a predicted alternate stop codon (p.T3033Nfs*11). This mutation has been described in multiple breast, ovarian and/or pancreatic cancer families across multiple ethnic groups (Serova-Sinilnikova OM et al. Am. J. Hum. Genet. 1997 May;60:1236-9; Machackova E et al. BMC Cancer. 2008 May;8:140; Kwong A et al. PLoS ONE. 2012 Sep;7:e43994; Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Holter S et al. J. Clin. Oncol. 2015 Oct;33:3124-9; Kwong A et al. J. Mol. Diagn. 2016 Jul;18(4):580-94; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Zhao Q et al. J. Gynecol. Oncol. 2017 Jul;28(4):e39; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). This mutation has also been reported in male patients with breast cancer and in a male patient with biliary tract cancer (Fostira F et al. Breast Cancer Res Treat. 2018 May;169(1):105-113; Wardell CP et al. J Hepatol. 2018 May;68(5):959-969; Momozawa Y et al. Nat Commun. 2018 Oct 4;9(1):4083). This mutation, in compound heterozygosity with another BRCA2 mutation, was also detected in a child with clinical features of Fanconi anemia (Kopic S et al. Acta Paediatr. 2011 May;100:780-3). Of note, this alteration is also designated as 9325insA and 9325dupA 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 (Nov 20, 2015)	criteria provided, single submitter (Shirts et al. (Genet Med 2016)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 Affected status: yes Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000266049.1 First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016	Number of individuals with the variant: 1 Clinical Features: multifocal breast cancer (present) Age: 50-59 years
Pathogenic (Apr 24, 2019)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hereditary breast ovarian cancer syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000605794.3 First in ClinVar: Aug 27, 2017 Last updated: Jul 06, 2020	Publications: PubMed (5) PubMed: 9150172‚ 25940717‚ 21138478‚ 22970155‚ 25682074 Comment: The p.Thr3033AsnfsX11 variant in BRCA2 has been reported in >20 individuals with BRCA2-associated cancers (Serova-Sinilnikova 1997, Kopic 2011, Kwong 2012, Holter 2015, Wong-Brown 2015, Breast … (more) The p.Thr3033AsnfsX11 variant in BRCA2 has been reported in >20 individuals with BRCA2-associated cancers (Serova-Sinilnikova 1997, Kopic 2011, Kwong 2012, Holter 2015, Wong-Brown 2015, Breast Cancer Information Core (BIC) database). This variant has been identified in 1/15908 African chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 3033 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282467.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4, PM2. (less) Number of individuals with the variant: 1
Pathogenic (Jul 03, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV002047738.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: The BRCA2 c.9097dupA; p.Thr3033AsnfsTer11 variant (rs397507419) has been reported in multiple individuals with breast or ovarian cancer (Kim 2012, Kwong 2012, Machackova 2008, Serova-Sinilnikova 1997, … (more) The BRCA2 c.9097dupA; p.Thr3033AsnfsTer11 variant (rs397507419) has been reported in multiple individuals with breast or ovarian cancer (Kim 2012, Kwong 2012, Machackova 2008, Serova-Sinilnikova 1997, Zhao 2017). It is reported as pathogenic in ClinVar (Variation ID: 38208), and is only observed on 3 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant introduces a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Kim H et al. Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer. Breast Cancer Res Treat. 2012; 134(3):1315-26. Kwong A et al. Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis. PLoS One. 2012; 7(9):e43994. Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008; 8:140. Serova-SInilnikova O et al. BRCA2 mutations in hereditary breast and ovarian cancer in France. Am J Hum Genet. 1997; 60(5):1236-9. Zhao Q et al. Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing. (less)
Pathogenic (Dec 30, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV002051549.3 First in ClinVar: Jan 08, 2022 Last updated: Feb 13, 2022	Comment: PVS1, PS4, PM2 Secondary finding: yes
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: SCV000838892.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (Feb 18, 2016)	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: SCV000488294.2 First in ClinVar: Nov 05, 2016 Last updated: Dec 24, 2022
Pathogenic (Mar 13, 2023)	criteria provided, single submitter (ACMG Variant Classification, Richards et al., 2015, Genet Med) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: no Allele origin: germline	Institute of Human Genetics, Heidelberg University Accession: SCV003936056.1 First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023	Sex: female
Pathogenic (Mar 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004041489.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Pathogenic (Jun 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV004238329.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Apr 28, 2023)	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 Accession: SCV004240374.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Mar 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211832.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Mar 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005196954.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jun 23, 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: SCV000695208.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (4) PubMed: 24916970‚ 22970155‚ 24010542‚ 22798144
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary Breast Carcinoma Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000693591.3 First in ClinVar: Mar 04, 2018 Last updated: Apr 22, 2020	Comment: This sequence change duplicates one base in exon 23 of BRCA2 mRNA (c.9097dupA), causing a frameshift after codon 3033 and the creation of a premature … (more) This sequence change duplicates one base in exon 23 of BRCA2 mRNA (c.9097dupA), causing a frameshift after codon 3033 and the creation of a premature translation stop signal 11 amino acid residues later p.(Thr3033Asnfs*11). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant is also known as c.9097_9098insA, 9325insA and 9317insA in the literature and has been reported in individuals affected with breast and ovarian cancer, pancreatic cancer, and Fanconi anemia (PMID: 22970155 , PMID: 9150172 PMID: 25940717 , PMID: 21138478). The mutation database ClinVar contains entries for this variant (Variation ID: 38208). (less)
Pathogenic (Jul 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579332.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PM1, PM2_SUP	Number of individuals with the variant: 1 Sex: female
Pathogenic (Oct 22, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Familial cancer of breast Affected status: unknown Allele origin: germline	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002757839.1 First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022
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: SCV000328046.4 First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022
Pathogenic (Jan 11, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV004025947.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023	Comment: PVS1, PP4, PM2_SUP
Pathogenic (Mar 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	See cases Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV004042782.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: ACMG criteria used to clasify this variant:PVS1, PS4_MOD, PM2_SUP Clinical Features: Clear cell carcinoma of kidney (present)
Pathogenic (Jul 26, 2023)	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: SCV000296658.6 First in ClinVar: Jun 24, 2016 Last updated: Jan 06, 2024	Publications: PubMed (38) PubMed: 26295337‚ 21138478‚ 25940717‚ 28324225‚ 28724667‚ 28993434‚ 29310832‚ 29335925‚ 29752822‚ 29907814‚ 30093976‚ 30287823‚ 30613976‚ 30702160‚ 30720243‚ 30720863‚ 30736435‚ 30875412‚ 31159747‚ 31214711‚ 31360904‚ 31396961‚ 31589614‚ 31742824‚ 31825140‚ 31957001‚ 32072338‚ 32338768‚ 32846166‚ 32959997‚ 33558524‚ 9150172‚ 22798144‚ 18489799‚ 22970155‚ 28692638‚ 28541631‚ 29360550 Comment: The BRCA2 c.9097dup (p.Thr3033Asnfs11) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant … (more) The BRCA2 c.9097dup (p.Thr3033Asnfs11) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 33558524 (2021), 32959997 (2020), 32846166 (2020), 22970155 (2012), ovarian cancer (PMID: 28541631 (2017)), and pancreatic cancer (PMID: 259407172015)). The variant has also been reported in a child with Fanconi Anemia (PMID: 21138478 (2011)). The frequency of this variant in the general population, 0.000012 (3/245952 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Feb 28, 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: SCV000684022.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (15) PubMed: 9150172‚ 18489799‚ 21138478‚ 22798144‚ 22970155‚ 24010542‚ 24916970‚ 25682074‚ 25940717‚ 28541631‚ 28692638‚ 29360550‚ 30287823‚ 31214711‚ 33471991 Comment: This variant inserts 1 nucleotide in exon 23 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known … (more) This variant inserts 1 nucleotide in exon 23 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9325insA, 9317insA and c.9090insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals and families affected with breast and ovarian cancer (PMID: 9150172, 18489799, 22798144, 22970155, 24010542, 24916970, 25682074, 28541631, 28692638, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001002) and additional individuals affected with pancreatic, prostate and biliary tract cancer (PMID: 25940717, 29360550, 31214711). This variant has been described as a recurrent mutation in hereditary breast and ovarian cancer families in the Chinese population (PMID: 22970155). This variant has also been reported in the compound heterozygous state in an individual affected with Fanconi anaemia (PMID: 21138478). 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. (less)
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: SCV002760735.5 First in ClinVar: Dec 17, 2022 Last updated: Aug 04, 2024
Pathogenic (Apr 10, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000210799.12 First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024	Comment: Frameshift 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) Frameshift 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 (PMID: 9150172, 12161607, 22798144, 25940717, 23569316, 29335925, 35264596); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9325dupA, 9317insA, or 9089_9090insA; This variant is associated with the following publications: (PMID: 12161607, 26852015, 26843898, 35534704, 32073954, 36555431, 34284872, 36637704, 36243179, 36721989, 34196900, 35864222, 28324225, 27882536, 32772980, 32599251, 32875559, 29922827, 9150172, 22970155, 21138478, 21913181, 23569316, 22798144, 18489799, 23242139, 25940717, 27157322, 27393621, 20383589, 25330149, 29752822, 29907814, 28692638, 28541631, 29335925, 28993434, 29310832, 30720863, 30287823, 30720243, 30702160, 30093976, 31159747, 31396961, 30736435, 31957001, 32072338, 32029870, 31214711, 32846166, 31589614, 31825140, 33558524, 32338768, 30875412, 30613976, 31742824, 32959997, 31360904, 31723001, 35418818, 33804961, 29360550, 31209999, 28724667, 35264596) (less)
Pathogenic (Jun 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368292.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PM5_STR Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Jun 08, 2013)	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: SCV000863757.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 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: SCV001954348.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Dec 01, 2018)	no assertion criteria provided Method: research	Ovarian neoplasm Affected status: yes Allele origin: somatic	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne Accession: SCV000923938.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019
Pathogenic (Sep 27, 2018)	no assertion criteria provided Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare Accession: SCV000925778.1 First in ClinVar: Jul 15, 2019 Last updated: Jul 15, 2019
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: SCV001451888.1 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	Malignant tumor of breast 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: SCV000592254.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021	Comment: The BRCA2 p.Thr3033Asnfs11 variant was identified in 9 of 10056 proband chromosomes (frequency: 0.0009) from Australian, Polish, French, Czech, Chinese, Greek and Korean individuals or … (more) The BRCA2 p.Thr3033Asnfs11 variant was identified in 9 of 10056 proband chromosomes (frequency: 0.0009) from Australian, Polish, French, Czech, Chinese, Greek and Korean individuals or families with triple negative breast cancer, (high risk) breast or ovarian cancer, HBOC, or pancreatic cancer (Wong 2015, Serova-Sinilnicova 1997, Machackova 2008, Kwong 2012, Konstantopoulou 2014, Kang 2015, Holter 2015). The variant was also identified in a 4 year old with Fanconi anemia with a hepatoblastoma (Kopic 2010). The variant was identified in dbSNP (ID: rs754205122) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, in ClinVar (as pathogenic, reviewed by an expert panel 2016 with 15 submitters), Clinvitae (7x), COGR (2x clinical laboratories), Cosmic (1x in a colon adenocarcinoma), LOVD 3.0 (1x), UMD-LSDB (19x as Causal, and as co-occurring with a pathogenic BRCA1 variant: c.3756_3759delGTCT, p.Ser1253ArgfsX10), BIC Database (27x with clinical importance classified pathogenic), and ARUP Laboratories (classified as definitely pathogenic). The variant was not identified in MutDB, or Zhejiang University database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.9097dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3033 and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in 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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001966901.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Jul 01, 2021)	no assertion criteria provided Method: research	Gastric cancer Affected status: unknown Allele origin: germline	Laboratory for Genotyping Development, RIKEN Accession: SCV002758299.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593
Pathogenic (Dec 04, 2023)	no assertion criteria provided Method: clinical testing	Malignant lymphoma, large B-cell, diffuse Affected status: yes Allele origin: somatic	Department Of Pathology & Laboratory Medicine, University Of Pennsylvania Accession: SCV004176811.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: Post-initial therapy specimen. Number of individuals with the variant: 1 Age: 50-59 years Sex: male Ethnicity/Population group: Caucasian Geographic origin: United States
Pathogenic (Mar 01, 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: SCV000054399.5 First in ClinVar: Apr 04, 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: SCV000587986.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017
Pathogenic (Apr 08, 2020)	no assertion criteria provided Method: research	Breast cancer, familial Affected status: yes Allele origin: germline	Center of Medical Genetics and Primary Health Care Accession: SCV000987249.3 First in ClinVar: Mar 01, 2020 Last updated: May 19, 2020	Comment: ACMG Guidelines 2015 criteria The BRCA2 variant p.Thr3033Asnfs is a known pathogenic variant in exon 23 in the Nucleic acid-binding OB-fold (T2968-3184L aa) domain, which … (more) ACMG Guidelines 2015 criteria The BRCA2 variant p.Thr3033Asnfs is a known pathogenic variant in exon 23 in the Nucleic acid-binding OB-fold (T2968-3184L aa) domain, which binds to single-stranded nucleic acids (staphylococcal nuclease and aspartyl-tRNA synthetase) or oligosaccharides (B subunits of enterotoxin and verotoxin-1), and has been termed the oligonucleotide/oligosaccharide binding motif, or OB fold (PMID: 12769718). This frameshift mutation disrupts the function of the domain which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This mutation hotspot has 31 pathogenic variants (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). 1 pathogenic prediction from GERP versus no benign predictions supports its deleterious effect (PP3 Pathogenic Supporting). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282467.1) (PP5 Pathogenic Supporting). The variant p.Thr3033Asnfs was found in a 48-year-old female with unilateral breast cancer and a strong family history. (less) Age: 40-49 years Sex: female
Pathogenic (Aug 08, 2021)	no assertion criteria provided Method: clinical testing	Breast carcinoma (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences Accession: SCV001774855.1 First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021	Age: 30-39 years Sex: female
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001906053.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021
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: SCV004243851.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
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Comment:

This sequence change creates a premature translational stop signal (p.Thr3033Asnfs*11) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer, pancreatic cancer, and Fanconi anemia (PMID: 9150172, 21138478, 22970155, 25940717). This variant is also known as c.9097_9098insA, 9325insA and 9317insA. ClinVar contains an entry for this variant (Variation ID: 38208). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.9097dupA pathogenic mutation, located in coding exon 22 of the BRCA2 gene, results from a duplication of one nucleotide at position 9097, causing a translational frameshift with a predicted alternate stop codon (p.T3033Nfs*11). This mutation has been described in multiple breast, ovarian and/or pancreatic cancer families across multiple ethnic groups (Serova-Sinilnikova OM et al. Am. J. Hum. Genet. 1997 May;60:1236-9; Machackova E et al. BMC Cancer. 2008 May;8:140; Kwong A et al. PLoS ONE. 2012 Sep;7:e43994; Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Holter S et al. J. Clin. Oncol. 2015 Oct;33:3124-9; Kwong A et al. J. Mol. Diagn. 2016 Jul;18(4):580-94; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Zhao Q et al. J. Gynecol. Oncol. 2017 Jul;28(4):e39; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). This mutation has also been reported in male patients with breast cancer and in a male patient with biliary tract cancer (Fostira F et al. Breast Cancer Res Treat. 2018 May;169(1):105-113; Wardell CP et al. J Hepatol. 2018 May;68(5):959-969; Momozawa Y et al. Nat Commun. 2018 Oct 4;9(1):4083). This mutation, in compound heterozygosity with another BRCA2 mutation, was also detected in a child with clinical features of Fanconi anemia (Kopic S et al. Acta Paediatr. 2011 May;100:780-3). Of note, this alteration is also designated as 9325insA and 9325dupA 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 p.Thr3033AsnfsX11 variant in BRCA2 has been reported in >20 individuals with BRCA2-associated cancers (Serova-Sinilnikova 1997, Kopic 2011, Kwong 2012, Holter 2015, Wong-Brown 2015, Breast Cancer Information Core (BIC) database). This variant has been identified in 1/15908 African chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the proteinâ€™s amino acid sequence beginning at position 3033 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282467.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4, PM2.

Comment:

The BRCA2 c.9097dupA; p.Thr3033AsnfsTer11 variant (rs397507419) has been reported in multiple individuals with breast or ovarian cancer (Kim 2012, Kwong 2012, Machackova 2008, Serova-Sinilnikova 1997, Zhao 2017). It is reported as pathogenic in ClinVar (Variation ID: 38208), and is only observed on 3 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant introduces a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Kim H et al. Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer. Breast Cancer Res Treat. 2012; 134(3):1315-26. Kwong A et al. Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis. PLoS One. 2012; 7(9):e43994. Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008; 8:140. Serova-SInilnikova O et al. BRCA2 mutations in hereditary breast and ovarian cancer in France. Am J Hum Genet. 1997; 60(5):1236-9. Zhao Q et al. Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing.

Comment:

This sequence change duplicates one base in exon 23 of BRCA2 mRNA (c.9097dupA), causing a frameshift after codon 3033 and the creation of a premature translation stop signal 11 amino acid residues later p.(Thr3033Asnfs*11). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant is also known as c.9097_9098insA, 9325insA and 9317insA in the literature and has been reported in individuals affected with breast and ovarian cancer, pancreatic cancer, and Fanconi anemia (PMID: 22970155 , PMID: 9150172 PMID: 25940717 , PMID: 21138478). The mutation database ClinVar contains entries for this variant (Variation ID: 38208).

Comment:

The BRCA2 c.9097dup (p.Thr3033Asnfs*11) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 33558524 (2021), 32959997 (2020), 32846166 (2020), 22970155 (2012), ovarian cancer (PMID: 28541631 (2017)), and pancreatic cancer (PMID: 259407172015)). The variant has also been reported in a child with Fanconi Anemia (PMID: 21138478 (2011)). The frequency of this variant in the general population, 0.000012 (3/245952 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Comment:

This variant inserts 1 nucleotide in exon 23 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9325insA, 9317insA and c.9090insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals and families affected with breast and ovarian cancer (PMID: 9150172, 18489799, 22798144, 22970155, 24010542, 24916970, 25682074, 28541631, 28692638, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001002) and additional individuals affected with pancreatic, prostate and biliary tract cancer (PMID: 25940717, 29360550, 31214711). This variant has been described as a recurrent mutation in hereditary breast and ovarian cancer families in the Chinese population (PMID: 22970155). This variant has also been reported in the compound heterozygous state in an individual affected with Fanconi anaemia (PMID: 21138478). 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.

Comment:

Frameshift 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 (PMID: 9150172, 12161607, 22798144, 25940717, 23569316, 29335925, 35264596); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9325dupA, 9317insA, or 9089_9090insA; This variant is associated with the following publications: (PMID: 12161607, 26852015, 26843898, 35534704, 32073954, 36555431, 34284872, 36637704, 36243179, 36721989, 34196900, 35864222, 28324225, 27882536, 32772980, 32599251, 32875559, 29922827, 9150172, 22970155, 21138478, 21913181, 23569316, 22798144, 18489799, 23242139, 25940717, 27157322, 27393621, 20383589, 25330149, 29752822, 29907814, 28692638, 28541631, 29335925, 28993434, 29310832, 30720863, 30287823, 30720243, 30702160, 30093976, 31159747, 31396961, 30736435, 31957001, 32072338, 32029870, 31214711, 32846166, 31589614, 31825140, 33558524, 32338768, 30875412, 30613976, 31742824, 32959997, 31360904, 31723001, 35418818, 33804961, 29360550, 31209999, 28724667, 35264596)

Comment:

The BRCA2 p.Thr3033Asnfs*11 variant was identified in 9 of 10056 proband chromosomes (frequency: 0.0009) from Australian, Polish, French, Czech, Chinese, Greek and Korean individuals or families with triple negative breast cancer, (high risk) breast or ovarian cancer, HBOC, or pancreatic cancer (Wong 2015, Serova-Sinilnicova 1997, Machackova 2008, Kwong 2012, Konstantopoulou 2014, Kang 2015, Holter 2015). The variant was also identified in a 4 year old with Fanconi anemia with a hepatoblastoma (Kopic 2010). The variant was identified in dbSNP (ID: rs754205122) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, in ClinVar (as pathogenic, reviewed by an expert panel 2016 with 15 submitters), Clinvitae (7x), COGR (2x clinical laboratories), Cosmic (1x in a colon adenocarcinoma), LOVD 3.0 (1x), UMD-LSDB (19x as Causal, and as co-occurring with a pathogenic BRCA1 variant: c.3756_3759delGTCT, p.Ser1253ArgfsX10), BIC Database (27x with clinical importance classified pathogenic), and ARUP Laboratories (classified as definitely pathogenic). The variant was not identified in MutDB, or Zhejiang University database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.9097dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3033 and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in 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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Comment:

ACMG Guidelines 2015 criteria The BRCA2 variant p.Thr3033Asnfs is a known pathogenic variant in exon 23 in the Nucleic acid-binding OB-fold (T2968-3184L aa) domain, which binds to single-stranded nucleic acids (staphylococcal nuclease and aspartyl-tRNA synthetase) or oligosaccharides (B subunits of enterotoxin and verotoxin-1), and has been termed the oligonucleotide/oligosaccharide binding motif, or OB fold (PMID: 12769718). This frameshift mutation disrupts the function of the domain which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This mutation hotspot has 31 pathogenic variants (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). 1 pathogenic prediction from GERP versus no benign predictions supports its deleterious effect (PP3 Pathogenic Supporting). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282467.1) (PP5 Pathogenic Supporting). The variant p.Thr3033Asnfs was found in a 48-year-old female with unilateral breast cancer and a strong family history.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.	Usui Y	The New England journal of medicine	2023	PMID: 36988593
Germline mutational spectrum in Armenian breast cancer patients suspected of hereditary breast and ovarian cancer.	Moradian MM	Human genome variation	2021	PMID: 33558524
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Screening of germline mutations in young Rwandan patients with breast cancers.	Uyisenga JP	Molecular genetics & genomic medicine	2020	PMID: 32959997
Next generation sequencing analysis of BRCA1 and BRCA2 identifies novel variations in breast cancer.	Yildiz Tacar S	Life sciences	2020	PMID: 32846166
Rare germline genetic variants and risk of aggressive prostate cancer.	Nguyen-Dumont T	International journal of cancer	2020	PMID: 32338768
The spectrum of BRCA1 and BRCA2 mutations and clinicopathological characteristics in Chinese women with early-onset breast cancer.	Chen L	Breast cancer research and treatment	2020	PMID: 32072338
BRCA1 c.5470_5477del, a founder mutation in Chinese Han breast cancer patients.	Meng H	International journal of cancer	2020	PMID: 31957001
Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients.	Gao X	Human mutation	2020	PMID: 31825140
Prevalence of hereditary breast and ovarian cancer (HBOC) predisposition gene mutations among 882 HBOC high-risk Chinese individuals.	Shao D	Cancer science	2020	PMID: 31742824
BRCA2 loss-of-function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese.	Ko JM	International journal of cancer	2020	PMID: 31396961
Germline Pathogenic Variants in 7636 Japanese Patients With Prostate Cancer and 12 366 Controls.	Momozawa Y	Journal of the National Cancer Institute	2020	PMID: 31214711
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers.	Yost S	JNCI cancer spectrum	2019	PMID: 31360904
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747
Discoveries beyond BRCA1/2: Multigene testing in an Asian multi-ethnic cohort suspected of hereditary breast cancer syndrome in the real world.	Ow SGW	PloS one	2019	PMID: 30875412
Hereditary Pancreatic Cancer: A Retrospective Single-Center Study of 5143 Italian Families with History of BRCA-Related Malignancies.	Toss A	Cancers	2019	PMID: 30736435
Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China.	Deng M	International journal of cancer	2019	PMID: 30720863
High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering.	Soussi T	Human mutation	2019	PMID: 30720243
Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients.	Bhaskaran SP	International journal of cancer	2019	PMID: 30702160
Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy.	Rizzolo P	International journal of cancer	2019	PMID: 30613976
Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer.	Li JY	International journal of cancer	2019	PMID: 29752822
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.	Momozawa Y	Nature communications	2018	PMID: 30287823
Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers.	Chan GHJ	Oncotarget	2018	PMID: 30093976
The germline mutational landscape of BRCA1 and BRCA2 in Brazil.	Palmero EI	Scientific reports	2018	PMID: 29907814
Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations.	Wardell CP	Journal of hepatology	2018	PMID: 29360550
Germline deleterious mutations in genes other than BRCA2 are infrequent in male breast cancer.	Fostira F	Breast cancer research and treatment	2018	PMID: 29335925
Comprehensive BRCA mutation analysis in the Greek population. Experience from a single clinical diagnostic center.	Apessos A	Cancer genetics	2018	PMID: 29310832
Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia.	Wen WX	Journal of medical genetics	2018	PMID: 28993434
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.	Sun J	Clinical cancer research : an official journal of the American Association for Cancer Research	2017	PMID: 28724667
The First Nationwide Multicenter Prevalence Study of Germline BRCA1 and BRCA2 Mutations in Chinese Ovarian Cancer Patients.	Wu X	International journal of gynecological cancer : official journal of the International Gynecological Cancer Society	2017	PMID: 28692638
Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing.	Zhao Q	Journal of gynecologic oncology	2017	PMID: 28541631
Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study.	Meisel C	Archives of gynecology and obstetrics	2017	PMID: 28324225
Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma.	Holter S	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2015	PMID: 25940717
Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer.	Wong-Brown MW	Breast cancer research and treatment	2015	PMID: 25682074
The role of targeted BRCA1/BRCA2 mutation analysis in hereditary breast/ovarian cancer families of Portuguese ancestry.	Peixoto A	Clinical genetics	2015	PMID: 24916970
High prevalence of BRCA1 founder mutations in Greek breast/ovarian families.	Konstantopoulou I	Clinical genetics	2014	PMID: 24010542
Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis.	Kwong A	PloS one	2012	PMID: 22970155
Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer.	Kim H	Breast cancer research and treatment	2012	PMID: 22798144
Hepatoblastoma in a 4-year-old girl with Fanconi anaemia.	Kopic S	Acta paediatrica (Oslo, Norway : 1992)	2011	PMID: 21138478
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
Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer.	Machackova E	BMC cancer	2008	PMID: 18489799
BRCA2 mutations in hereditary breast and ovarian cancer in France.	Serova-Sinilnikova OM	American journal of human genetics	1997	PMID: 9150172
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Text-mined citations for rs397507419 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.9097dup (p.Thr3033fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs397507419 ...