rs397508041

Variant names:

• chr13-32380135-G-GA
• rs80359752
• NM_000059.4:c.9253dupA

Your query was ambiguous. Multiple possible variants found:

• chr13-32380135-G-GA
• chr13-32380135-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9253dupA​(p.Thr3085AsnfsTer26) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,458,716 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift, splice_region
• Clinical Significance: Pathogenic reviewed by expert panel P:29
• Conservation: PhyloP100: 4.00

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32380135-G-GA is Pathogenic according to our data. Variant chr13-32380135-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 38225.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9253dupA	p.Thr3085AsnfsTer26	frameshift_variant, splice_region_variant	Exon 24 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9253dupA	p.Thr3085AsnfsTer26	frameshift_variant, splice_region_variant	Exon 24 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8884dupA	p.Thr2962AsnfsTer26	frameshift_variant, splice_region_variant	Exon 24 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1311dupA		splice_region_variant, non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*1311dupA		3_prime_UTR_variant	Exon 23 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458716 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725646

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:29

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:12

Jul 01, 2015

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 16, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM5_PTC_Strong -

Dec 11, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9246_9247dupA (p.Thr3085Asnfs*26) frameshift variant in BRCA2 has been reported in multiple unrelated patients with breast, ovarian or prostate cancer [PMID 11389159, 16455195, 16683254, 21952622,22798144, 25330149]. Based on the current evidence, this variant is classified as pathogenic -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 21, 2023

deCODE genetics, Amgen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant NM_000059.4:c.9253dup (chr13:32380135) in BRCA2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. -

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:6

Oct 11, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant causes the premature termination of BRCA2 protein synthesis. In the published literature, it has been reported in individuals affected with breast and/or ovarian cancer, prostate cancer, and esophageal cancer (PMIDs: 11389159 (2001), 21952622 (2011), 22798144 (2012), 29915322 (2018), 30322717 (2018), 31396961 (2019), 30702160 (2019), and 30972954 (2019)). Based on the available information, this variant is classified as pathogenic. -

Sep 11, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 9481insA, 9481dupA, and 9474insA; This variant is associated with the following publications: (PMID: 22798144, 23034506, 16455195, 26287763, 21120943, 25330149, 30702160, 30322717, 32854451, 23569316, 11920643, 20104584, 19656164, 18824701, 11389159, 16683254, 21952622, 26681312, 25863477, 22720145, 28008555, 27836010, 28152038, 11802209, 7627958, 30972954, 29310832, 28724667, 29915322, 29339979, 30720243, 31396961, 29625052, 31447099, 32832836) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Thr3085AsnfsX26 variant was identified in 13 of 20330 proband chromosomes (frequency: 0.0006) from German, Danish, Korean, American, and British individuals or families with (sporadic, high risk, early onset, or male) breast cancer, sporadic or familial ovarian cancer or prostate cancer (Meindl_2002_11802209, Bergthorsson_2001_11389159, Kang_2015_25863477 , Kim_2012_22798144, Pal_2015_26287763 , Pritzlaff_2016_28008555, Kote-Jarai_2011_21952622, Rebbeck_2016_27836010, Borg_2010_20104584, Cybulski_2015_25330149). In a study looking at transheterozygosity (inheritance of pathogenic mutations in both BRCA1 and BRCA2), the variant was identified in 1 Italian proband with breast cancer, co-occurring with BRCA1 c.3228_3229delAG (Rebbeck_2016_27836010). The variant was also identified in dbSNP (ID: rs80359752) “With Pathogenic allele”, ClinVar (classified pathogenic, reviewed by an expert panel (2016); submitters: pathogenic by ENIGMA, CIMBA, Fulgent Genetics, Ambry Genetics, GeneDx, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, Invitae, Dept. of Medical Genetics (Oslo University Hospital), BIC and SCRP (Sharing Clinical Reports Project); and likely pathogenic by Counsyl), Clinvitae (4x), GeneInsight-COGR (classified pathogenic by 2 clinical laboratories), LOVD 3.0 (1x), UMD-LSDB (5x causal), BIC Database (19x, with clinical importance, class 5 (pathogenic)), ARUP Laboratories (5-definitely pathogenic), Zhejiang Colon Cancer Database; the variant was not identified in Cosmic, MutDB, 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.9253dupA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3085 and leads to a premature stop codon at position 3110. 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 laboratory’s criteria to be classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Sep 14, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.9253dupA (p.Thr3085AsnfsX26) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 248942 control chromosomes. c.9253dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Bergthorsson_2001, Inoue_1997, Kim_2012, Pal_2015, Rebbeck_2016). These data indicate that the variant is very likely to be associated with disease. At-least one trans heterozygous co-occurrence with another pathogenic variant has been reported (BRCA1 c.3226_3227AG (reported as NM_007294:c.3228_3229delAG), p.Gly1077fs) (Rebbeck_2016). Thirteen clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr3085Asnfs*26) 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 (rs80359752, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 11389159, 16455195, 16683254, 19656164, 21952622, 22798144, 23569316, 25330149). This variant is also known as 9474insA, 9481insA, 9253insA, and c.9253_9254insA. ClinVar contains an entry for this variant (Variation ID: 38225). For these reasons, this variant has been classified as Pathogenic. -

Apr 20, 2017

Department of Pathology and Molecular Medicine, Queen's University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Nov 22, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 24 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9246_9247insA, 9474insA and 9481insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals and families affected with breast and/or ovarian cancer (PMID: 11389159, 16683254, 20104584, 22798144, 25330149, 25863477, 26287763, 28008555, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001724) and two individuals affected with prostate cancer (PMID: 23569316). This variant has been identified in 2/243602 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. -

Aug 14, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9253dupA (p.T3085Nfs*26) alteration, located in exon 24 (coding exon 23) of the BRCA2 gene, consists of a duplication of A at position 9253, causing a translational frameshift with a predicted alternate stop codon after 26 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This alteration has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Bergthorsson, 2001; Meindl, 2002; Kim, 2012; Kang, 2015; Pal, 2015). This mutation has also been detected in a male with early-onset prostate cancer (Kote-Jarai, 2011) and in a male breast cancer patient (Pritzlaff, 2017). Of note, this alteration is also designated as c.9253insA, c.9253_9254insA, and c.9474insA in published literature. Based on the available evidence, this alteration is classified as pathogenic. -

BRCA2-related cancer predisposition Pathogenic:1

Feb 28, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 24 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9246_9247insA, 9474insA and 9481insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals and families affected with breast and/or ovarian cancer (PMID: 11389159, 16683254, 20104584, 22798144, 25330149, 25863477, 26287763, 28008555, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001724) and two individuals affected with prostate cancer (PMID: 23569316). This variant has been identified in 2/243602 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. -

BRCA2-related disorder Pathogenic:1

Jul 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.9253dupA variant is predicted to result in a frameshift and premature protein termination (p.Thr3085Asnfs*26). This variant (also reported as 9253insA, 9481dupA & 9474insA) has been reported in many individuals with various cancers, including breast/ovarian cancer (Bergthorsson et al. 2001. PubMed ID: 11389159; Table S1, Borg et al. 2010. PubMed ID: 20104584; Table 4, Kim et al. 2012. PubMed ID: 22798144; Table S1, Carter et al. 2018. PubMed ID: 30322717), prostate cancer (Table A1, Castro et al. 2013. PubMed ID: 23569316; Table S2, Matejcic et al. 2020. PubMed ID: 32832836), biliary tract cancer (Power et al. 2020. PubMed ID: 32918181), lung and esophageal squamous cell carcinoma (Table S2A, Huang et al. 2018. PubMed ID: 29625052), and renal cell carcinoma (Yngvadottir et al. 2022. PubMed ID: 35441217). It has also been reported as pathogenic by multiple sources in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38225/). This variant is reported in 0.00089% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

May 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:1

Mar 07, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ovarian neoplasm Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80359752; hg19: chr13-32954272;