rs80359473

chr13-32339287-AAAAG-A

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.4936_4939del(p.Glu1646GlnfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,568 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. K1645K) has been classified as Likely benign. 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
• Clinical Significance: Pathogenic reviewed by expert panel P:25
• Conservation: PhyloP100: 1.07

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 13-32339287-AAAAG-A is Pathogenic according to our data. Variant chr13-32339287-AAAAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 37935.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339287-AAAAG-A is described in Lovd as [Pathogenic]. Variant chr13-32339287-AAAAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.4936_4939del	p.Glu1646GlnfsTer23	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.4936_4939del	p.Glu1646GlnfsTer23	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454568 Hom.: 0 AF XY: 0.00000277 AC XY: 2 AN XY: 723264

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000464

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 17, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	This variant deletes 4 nucleotides in exon 11 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 in at least 10 heterozygous individuals affected with breast and ovarian cancer (PMID: 16030099, 17020472, 20104584, 21553119, 23479189, 26026974, 28503720, 29084914, 29560538, 33471991; Leiden Open Variation Database DB-ID BRCA2_001062, 34290354, 34645131, 34933735, Color internal data) and 3 individuals affected with pancreatic cancer (PMID: 30274973, Color internal data). This variant also has been observed in compound heterozygous state with a known pathogenic BRCA2 mutation in individuals affected with the recessive disease, Fanconi anemia (PMID: 15070707). 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. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Sep 23, 2016	- -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 15, 2021	The BRCA2 c.4936_4939delGAAA; p.Glu1646GlnfsTer23 variant (rs80359473, also known as 5164del4), is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancer and Fanconi anemia (de Juan 2015, de Juan Jimenez 2013, Esteban Cardenosa 2010, Gabaldo Barrios 2017, Infante 2006, Labidi-Galy 2018, Rummel 2017, Schayek 2018, Wagner 2004). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37935) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 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 to be pathogenic. References: de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015 Dec;14(4):505-13. de Juan Jimenez I et al. Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence. Fam Cancer. 2013 Dec;12(4):767-77. Esteban Cardenosa E et al. Broad BRCA1 and BRCA2 mutational spectrum and high incidence of recurrent and novel mutations in the eastern Spain population. Breast Cancer Res Treat. 2010 May;121(1):257-60. Gabaldo Barrios X et al. Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers. Fam Cancer. 2017 Oct;16(4):477-489. Infante M et al. High proportion of novel mutations of BRCA1 and BRCA2 in breast/ovarian cancer patients from Castilla-León (central Spain). J Hum Genet. 2006;51(7):611-7. Labidi-Galy SI et al. Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer. Clin Cancer Res. 2018 Jan 15;24(2):326-333. Rummel SK et al. Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer. Breast Cancer Res Treat. 2017 Aug;164(3):593-601. Schayek H et al. Mutational analysis of candidate genes in Israeli male breast cancer cases. Breast Cancer Res Treat. 2018 Jul;170(2):399-404. Wagner JE et al. Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and Fanconi anemia. Blood. 2004 Apr 15;103(8):3226-9. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2019	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 with a pathogenic BRCA2 variant on the opposite allele (in trans) in siblings with Fanconi anemia (Wagner 2004); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with BRCA2-related cancers (Kaufman 2006, Stegel 2011, Novakovic 2012, de Juan Jimenez 2013, de Juan 2015, Hoberg-Vetti 2015, Bunnell 2016, Bannon 2018); Also known as c.5164del4; This variant is associated with the following publications: (PMID: 24301060, 22430266, 27276934, 28127413, 30274973, 30293905, 21232165, 23479189, 15070707, 22923021, 26350514, 15689453, 26026974, 26656232, 20104584, 26681312, 16758124, 20033483, 16825431, 17020472, 27741520, 27160020, 28503720, 28637432, 29560538, 28477318, 29084914, 28152038, 29086229, 30014164, 30755392, 30720863, 30322717, 31159747) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 01, 2021	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in breast, ovarian, male breast and pancreatic cancer in the published literature (PMID: 30274973 (2018), 26026974 (2015), 22923021 (2012), 21232165 (2011), 17020472 (2006), 16030099 (2005)). This variant has also been reported in Fanconi Anemia patients (PMID: 15070707 (2004)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 15, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2017	- -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 03, 2019	Variant summary: BRCA2 c.4936_4939delGAAA (p.Glu1646GlnfsX23) 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. The variant was absent in 238878 control chromosomes (gnomAD). c.4936_4939delGAAA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Finkelman_2012, Infante_2006, Kaufman_2006, Krajc_2008, Borg_2010, Beristain_2010, de Juan Jimenez_2012, Novakovic_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Fourteen ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 09, 2021	This sequence change deletes 4 bases from exon 11 of the BRCA2 mRNA (c.4936_4939delGAAA), causing a frameshift after codon 1646. This creates a premature translational stop signal 23 amino acid residues later (p.(Glu1646Glnfs*23) and is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular variant is also known in the literature as c.4933_4936delAAAG and 5164del4 and has been described in the literature in families with breast and/or ovarian cancer and Fanconi anemia (PMID: 23479189, 22923021, 15070707,31159747). The mutation database Clinvar contains entries for this variant (Variation ID:37935). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Glu1646Glnfs*23) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 15070707, 20960228, 22923021, 23479189, 26350514). This variant is also known as c.4933_4936delAAAG and 5164del4. ClinVar contains an entry for this variant (Variation ID: 37935). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 15, 2016	The p.Glu1646fs variant in BRCA2 has been reported as heterozygous in >20 indivi duals with BRCA2-associated cancers and as compound heterozygous in 2 siblings w ith Fanconi anemia (H?berg-Vetti 2016, Jimenez 2013, Stegel 2011, Wagner 2004, B reast Cancer Information Core (BIC) database). It was absent from large populati on studies, though the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the pr otein?s amino acid sequence beginning at position 1646 and leads to a premature termination codon 23 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein. Heterozygous loss of function of the BR CA2 gene is an established disease mechanism in individuals with hereditary brea st and ovarian cancer (HBOC). In addition, this variant was classified as Pathog enic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar S CV000300803.2). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner . -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 26, 2023	This variant deletes 4 nucleotides in exon 11 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 in at least 10 heterozygous individuals affected with breast and ovarian cancer (PMID: 16030099, 17020472, 20104584, 21553119, 23479189, 26026974, 28503720, 29084914, 29560538, 33471991; Leiden Open Variation Database DB-ID BRCA2_001062, 34290354, 34645131, 34933735, Color internal data) and 3 individuals affected with pancreatic cancer (PMID: 30274973, Color internal data). This variant also has been observed in compound heterozygous state with a known pathogenic BRCA2 mutation in individuals affected with the recessive disease, Fanconi anemia (PMID: 15070707). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 27, 2023	The c.4936_4939delGAAA (p.E1646Qfs*23) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of 4 nucleotides from position 4936 to 4939, causing a translational frameshift with a predicted alternate stop codon after 23 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Weitzel, 2005; Kaufman, 2006; Infante, 2006; Borg, 2010; Stegel, 2011; Laitman, 2011; De Leeneer, 2012; Novakovi, 2012; de Juan Jiménez, 2013; Høberg-Vetti, 2016; Gabaldó Barrios, 2017; Bunnell, 2017; Baert, 2017; Rummel, 2017; Carter, 2018; Labidi-Galy, 2018; Deng, 2019; Palmer, 2020; Breast Cancer Association, 2021). This mutation has also been reported in a patient with early-onset pancreatic cancer (Bannon, 2018), as well as a male patient with transitional cell carcinoma (Kinget, 2021). Of note, this alteration is also designated as 5164del4, c.5164_5167del, and c.5164_5167delGAAA in published literature. Based on the available evidence, this alteration is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 11, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Aug 05, 2021	- -

Asthma;C0018681:Headache;C0028754:Obesity;C0029396:Ectopic ossification;C0149931:Migraine;C0151786:Muscle weakness;C0152459:Striae distensae;C0262630:Short attention span;C0392525:Nephrolithiasis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

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

Pathogenic, criteria provided, single submitter

clinical testing

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Apr 02, 2020

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Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 23, 2023

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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: rs80359473; hg19: chr13-32913424;