rs869312761

Variant names:

• chr13-32394863-CTG-C
• rs80359763
• NM_000059.4:c.9435_9436delGT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9435_9436delGT​(p.Ser3147CysfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. V3145V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:27
• Conservation: PhyloP100: -0.347
• Publications: 18 publications found

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]

BRCA2 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32394863-CTG-C is Pathogenic according to our data. Variant chr13-32394863-CTG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 38240.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.9435_9436delGT	p.Ser3147CysfsTer2	frameshift_variant	Exon 25 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9435_9436delGT	p.Ser3147CysfsTer2	frameshift_variant	Exon 25 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9066_9067delGT	p.Ser3024CysfsTer2	frameshift_variant	Exon 25 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1493_*1494delGT		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1493_*1494delGT		3_prime_UTR_variant	Exon 24 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251342 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461808 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7

Oct 10, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 15, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides in exon 25 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported several in individuals affected with breast or ovarian cancer (PMID: 8673090, 18489799, 21913181, 22798144, 24504028, 24549055, 25186627, 27153395, 27798748, 28008555). This variant has been identified in 1/251342 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. -

Nov 18, 2015

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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. -

Jun 06, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A known pathogenic mutation was detected in the BRCA2 gene (c.9435_9436delGT). This sequence change creates a premature translational stop signal (p.Ser3147Cysfs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in gnomAD genomes. This variant has been reported in individuals affected with breast cancer (PMID: 8673090, 22798144, 18489799, 21913181), ovarian cancer (PMID: 24504028), and an individual with male breast cancer and melanoma (PMID: 28008555). This variant is also known as 9433delGT, 9663delGT and 3144_3145del in the literature. ClinVar contains an entry for this variant (Variation ID: 38240) with 17 submissions, all of which describe it as pathogenic, 3 stars, reviewed by expert panel. Lossof- function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic. -

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

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:6

Jul 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9435_9436delGT; p.Ser3147CysfsTer2 variant (rs864622235), also known as 9433_9434del and 9663_9664del, has been published in the medical literature in multiple individuals with breast cancer and families with HBOC (Kim 2012, Litton 2012, Machackova 2008, Phelan 1996). This variant is also reported in ClinVar (Variation ID: 38240). This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant creates a frameshift by deleting 2 nucleotides, 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 Aug;134(3):1315-26. Litton JK et al. Earlier age of onset of BRCA mutation-related cancers in subsequent generations. Cancer. 2012 Jan 15;118(2):321-5. 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 May 20;8:140. Phelan CM et al. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet. 1996 May;13(1):120-2. -

Mar 06, 2024

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified by standard clinical testing. female patient with breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1 -

Sep 21, 2021

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 addition, it has been described in families with hereditary breast and ovarian cancer syndrome and in individuals with breast cancer and/or ovarian cancer ((PMID: 29446198 (2018), 28008555 (2017), 27798748 (2017), 22798144 (2012), 21913181 (2012), 18489799 (2008), 8673090 (1996)). Based on the available information, this variant is classified as pathogenic. -

Sep 10, 2023

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; 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; Observed in individuals with personal or family history of BRCA2-associated cancers (PMID: 8673090, 22798144, 24504028, 26962171); Also known as 9433delGT, 9663_9664delGT, and 9663delGT; This variant is associated with the following publications: (PMID: 30122538, 29922827, 28888541, 10570174, 15131399, 18489799, 8673090, 24504028, 22798144, 26962171, 28008555, 30293905, 21913181, 30720243, 31447099, 30787465, 33087929, 31892343, 31723001, 32295079, 33471991, 36623239, 34326862, 29446198, 20051372, 35186721, 35464868, 27798748, 24549055, 20104584, 19941162, 37528630) -

Jun 28, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP5, PM2, PVS1 -

May 25, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Feb 02, 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.Ser3147Cysfs*2) 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 (rs80359763, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer and male breast cancer and melanoma (PMID: 8673090, 18489799, 21913181, 22798144, 24504028, 28008555). This variant is also known as 9433delGT, 9663delGT and 3144_3145del. ClinVar contains an entry for this variant (Variation ID: 38240). For these reasons, this variant has been classified as Pathogenic. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser3147CysfsX2 variant in BRCA2 has been reported in >20 individuals with breast cancer (Cunningham 2014, Phelan 1996, BIC database). It has also been identified in 1/113672 European chromosomes by 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 protein’s amino acid sequence beginning at position 3147 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 38240). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4. -

Jan 02, 2021

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.9435_9436delGT (p.Ser3147CysfsX2) 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 251342 control chromosomes. c.9435_9436delGT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple 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 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:3

Jun 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9435_9436delGT pathogenic mutation, located in coding exon 24 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 9435 to 9436, causing a translational frameshift with a predicted alternate stop codon (p.S3147Cfs*2). This mutation was first reported in a Canadian high-risk breast cancer family (Phelan CM et al. Nat. Genet. 1996 May;13:120-2). It has also been described in a Korean cohort of high-risk breast cancer families (Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26), as well as other HBOC families (Lubinski J et al. Fam. Cancer. 2004;3:1-10; Litton JK et al. Cancer. 2012 Jan;118:321-5). Of note, this alteration is also designated as 9433delGT and 9663delGT 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. -

Nov 23, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 14, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 2 nucleotides in exon 25 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported several in individuals affected with breast or ovarian cancer (PMID: 8673090, 18489799, 21913181, 22798144, 24504028, 24549055, 25186627, 27153395, 27798748, 28008555), and it has also been detected in a breast cancer case-control meta-analysis in 5/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; LOVD DB-ID BRCA2_000942). This variant has been identified in 1/251342 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. -

Breast and/or ovarian cancer Pathogenic:2

Dec 09, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

May 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Pathogenic:1

Aug 15, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9435_9436delGT (p.Ser3147CysfsTer2) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Ser3147CysfsTer2 variant has been found in a heterozygous state in at least four patients with hereditary breast and ovarian cancer (HBOC), including in one male with breast cancer, in two individuals with breast and/or ovarian cancer and in one individual with ovarian cancer (Kim et al. 2012; Litton et al. 2012; Cunningham et al. 2014; Pritzlaff et al. 2017). The variant was also identified in a heterozygous state in three at-risk individuals with a family history of early-onset breast and ovarian cancer (Lubinski et al. 2004; Machackova et al. 2008; Bellacosa et al. 2010). This variant has not been described in the literature in patients with Fanconi anemia (FA), however, it is generally accepted that heterozygous variants pathogenic for HBOC confer carrier status for FA. Control data are unavailable for this variant which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence and the potential impact of frameshift variants, the p.Ser3147CysfsTer2 variant is classified as pathogenic for BRCA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Familial cancer of breast Pathogenic:1

Feb 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.35
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80359763; hg19: chr13-32969000; COSMIC: COSV105326672; COSMIC: COSV105326672;