rs276174813

Positions:

• chr13-32333271-CATCTT-C

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.1796_1800del​(p.Ser599Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,454,666 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. T598T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:25
• Conservation: PhyloP100: 2.08

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 13-32333271-CATCTT-C is Pathogenic according to our data. Variant chr13-32333271-CATCTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 37756.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32333271-CATCTT-C is described in Lovd as [Pathogenic]. Variant chr13-32333271-CATCTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1796_1800del	p.Ser599Ter	frameshift_variant	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1796_1800del	p.Ser599Ter	frameshift_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000410 AC: 1 AN: 244054 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132144

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454666 Hom.: 0 AF XY: 0.00000276 AC XY: 2 AN XY: 723478

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:25

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	The c.1796_1800del (p.Ser599*) variant in the BRCA2 gene has been detected multiple patients with breast cancer [reported as 2022del5 in PMID 8988179]. This variant creates a premature stop codon at amino acid position 599 of the BRCA2 protein. This variant is thus predicted to result in a loss of function of the protein. This variant has not been observed in the ExAC population database. This variant thus classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Cancer Genomics Laboratory, City of Hope Comprehensive Cancer Center	Jan 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Dec 22, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated -
Pathogenic, criteria provided, single submitter	research	Laan Lab, Human Genetics Research Group, University of Tartu	May 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 20, 2017	- -
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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 02, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Dec 10, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 24, 2021	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals and families affected with breast/ovarian cancer in the published literature (PMID: 8988179 (1997), 22798144 (2012), 25371446 (2014), 29084914 (2018), 29335925 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; 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 2024_2028del, 2024del5, and c.1794_1798del; This variant is associated with the following publications: (PMID: 12142080, 29470806, 30014164, 31794323, 31336956, 34413315, 32438681, 32875559, 30040829, 8988179, 22009639, 22085629, 24549055, 11754111, 27062684, 28724667, 29907814, 29084914, 29335925, 25371446, 22798144, 18694767, 15887246, 11504767, 9150154, 26295337, 22762150, 31209999, 30720243, 30702160, 31396961, 31444830, 31957001, 31447099, 33726785, 31825140, 30787465, 31742824, 30130155, 34645131, 35535697, 32427313, 31871109) -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2020	The p.Ser599X variant (also reported as c.2022del5, c.2024_2028delCTTAT, and c.2024del5) in BRCA2 has been reported in the literature in >15 individuals with BRCA2-related cancers and segregated with disease in at least three relatives (Gayther 1997, Håkansson 1997, Loman 2001, Ladopoulou 2002, Armakolas 2002, Bonadona 2005, Tommasi 2008, Kim 2012, Castéra 2014, Torres-Mejía 2015, Azzollini 2016, Barnes-Kedar 2018, Fostira 2018, Palmero 2018,Singh 2018,Bhaskaran 2019). This vairant has been identified in 1/111114 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 599, which is 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 April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282361.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1; PM2; PS4, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 19, 2022	Variant summary: BRCA2 c.1796_1800delCTTAT (p.Ser599X) 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 4.1e-06 in 244054 control chromosomes. c.1796_1800delCTTAT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Kim_2012, Lang_2017, Palmer_2020). 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. 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	This sequence change creates a premature translational stop signal (p.Ser599*) 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 (rs276174813, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 8988179, 22009639, 22085629, 22798144, 24549055). This variant is also known as c.1796delCTTAT and 2024del5. ClinVar contains an entry for this variant (Variation ID: 37756). 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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 22, 2021	The c.1796_1800delCTTAT pathogenic mutation (also known as p.S599*), located in coding exon 9 of the BRCA2 gene, results from a deletion of five nucleotides at positions 1796 to 1800. This changes the amino acid from a serine to a stop codon within coding exon 9. This mutation has been detected in female breast cancer, male breast cancer, and ovarian cancer cases (Gayther SA et al. Nat. Genet. 1997 Jan;15:103-5; Loman N et al. J. Natl. Cancer Inst. 2001 Aug;93:1215-23; Ladopoulou A et al. Cancer Lett. 2002 Nov;185:61-70; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Torres-Mejia G et al. Cancer Epidemiol. Biomarkers Prev. 2015 Mar;24:498-505; Fostira F et al. Breast Cancer Res. Treat. 2018 May;169:105-113; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24:326-333). Of note, this alteration is also designated as 2024del5 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2022	This variant deletes 5 nucleotides in exon 10 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 15 individuals affected with breast, ovarian and/or endometrial cancer (PMID: 9150154, 11754111, 12142080, 15887246, 18694767, 18752448, 22009639, 25371446, 29084914, 33471991; Leiden Open Variation Database DB-ID BRCA2_001800, 33629534, 34657357, 34645131). This variant has been identified in 1/244054 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. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 14, 2021

- -

BRCA2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2024

The BRCA2 c.1796_1800del5 variant is predicted to result in premature protein termination (p.Ser599*). This variant has been reported to be causative for breast or ovarian cancer (described as c.2022del5, Gayther et al 1997. PubMed ID: 8988179; Azzollini. 2016. PubMed ID: 27062684 ; Table S2, Fostira. 2018. PubMed ID: 29335925). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37756/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Ser599X variant was identified in 2 of 816 proband chromosomes (frequency: 0.002) from individuals or families with breast and ovarian cancer (Gayther 1997, Bayraktar 2012). The variant was also identified in dbSNP (ID: rs276174813) “With pathogenic allele”, HGMD, the ClinVar database (classified as a pathogenic variant by the BIC and Invitae), GeneInsight VariantWire database (1X, classified as “pathogenic” by a clinical laboratory), the BIC database (12X with clinical importance) and UMD (15X as a causal variant). The p.Ser599X variant leads to a premature stop codon at position 599, which is predicted to lead to 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs276174813; hg19: chr13-32907408;