rs80359391

Positions:

• chr13-32337952-CTG-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.3599_3600del​(p.Cys1200Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,754 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. C1200C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:27
• Conservation: PhyloP100: 0.187

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32337952-CTG-C is Pathogenic according to our data. Variant chr13-32337952-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 51493.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337952-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-32337952-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.3599_3600del	p.Cys1200Ter	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.3599_3600del	p.Cys1200Ter	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251042 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461754 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 727162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 15, 2016	- -
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, 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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	A known pathogenic variant was detected in the BRCA2 gene (p.Cys1200Ter). This sequence change creates a premature translational stop signal (p.Cys1200*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in individuals with breast cancer, ovarian cancer, and Fanconi anemia (PMID: 24504028, 16683254, 25863477, 15645491, 24728189). This variant is also known as 3827delGT in the literature. ClinVar contains an entry for this variant (Variation ID: 51493) with 16 submissions, all pathogenic, 3 stars, no conflict, and reviewed by an expert panel. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Cys1200X variant was identified by De Leon Matsuda (2002) in one individual with breast cancer and in one control subject with a “suspicious breast mass” which was interpreted as fibrocystic disease, though a biopsy was not taken from the control subject. The variant was also identified in dbSNP (ID: rs80359391), HGMD, and UMD (3X as a causal variant). The p.Cys1200X variant leads to a premature stop codon at position 1200, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM5_PTC_Strong -

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 30, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2022	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; Observed in individuals with BRCA2-related cancers (De Leon Matsuda et al., 2002; Liede et al., 2002; Song et al., 2014; Kang et al., 2015; Nielsen et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3827delGT; This variant is associated with the following publications: (PMID: 26833046, 32455662, 32980694, 31492746, 29922827, 34697415, 11920621, 12442265, 22798144, 24728189, 24504028, 26287763, 25863477, 26681312, 28166811, 27767231, 28617445, 29128982, 29348823, 29470806, 29446198, 30309222, 30287823, 30720243, 30702160, 30322717, 30972954, 31263054, 29176636, 33646313, 33372952, 33151324, 30787465, 31742824, 33087929, 34645131, 15645491) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 16, 2020	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in symptomatic individuals with breast and/or ovarian cancer and a boy with a phenotype of Fanconi Anemia in the published literature (PMIDs: 22798144 (2012), 24259538 (2014), 24728189 (2014), 26287763 (2015), 29348823 (2017), 30309222 (2019), and 30702160 (2019)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 21, 2019	- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Cys1200X variant in BRCA2 (resulting from c.3599_3600delGT) has been reported in at least 13 individuals with BRCA2-related cancers (De Leon Matsuda 2002, Cunningham 2014, Susswein 2016, Hirasawa 2017, Momozawa 2018, BIC database). It has also been identified in 1/18394 East Asian 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 frameshift variant is predicted to lead to a premature termination codon at position 1200. 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 Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 51493). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. -
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	Invitae	Dec 22, 2023	This sequence change creates a premature translational stop signal (p.Cys1200*) 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 (rs80359391, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and Fanconi anemia (PMID: 15645491, 16683254, 24504028, 24728189, 25863477). This variant is also known as 3827delGT. ClinVar contains an entry for this variant (Variation ID: 51493). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 07, 2021	Variant summary: BRCA2 c.3599_3600delGT (p.Cys1200X) 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 1.6e-05 in 254218 control chromosomes. c.3599_3600delGT has been widely 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 25, 2023	This variant deletes 2 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 individuals affected with breast and/or ovarian cancer (PMID: 11920621, 12774040, 20104584, 22798144, 24504028, 24728189, 26287763, 29348823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001069) and 2 individuals affected with prostate cancer (PMID: 31214711). This variant has been detected in a compound heterozygous carrier affected with Fanconi anemia (PMID: 15645491). This variant also has been detected in unaffected individuals (PMID: 11920621, 30287823, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA2_001069) and in 4/251042 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 19, 2022	The c.3599_3600delGT pathogenic mutation (also known as p.C1200*), located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at positions 3599 to 3600. This changes the amino acid from a cysteine to a stop codon within coding exon 10. This mutation has been reported in multiple individuals diagnosed with breast or ovarian cancer (De Leon Matsuda ML et al. Int. J. Cancer. 2002 Apr;98:596-603; Hamann U et al. Eur. J. Hum. Genet. 2003 Jun;11:464-7; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Kang E et al. Breast Cancer Res Treat. 2015 May;151:157-68; Hirasawa A et al. Oncotarget. 2017 Dec;8:112258-112267; Kwon BS et al. Cancer Res Treat. 2018 Oct; Lovejoy LA et al. Austin J Cancer Clin Res. 2018 Jun; 5(1):1082; Bhaskaran SP et al. Int J Cancer. 2019 Jan). This mutation has also been reported in a child with biallelic BRCA2 related Fanconi Anemia who was diagnosed with leukemia by the age of 2 years (Meyer S et al. Genes Chromosomes Cancer. 2005 Apr;42:404-15). Of note, this alteration is also designated as 3827delGT 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. -

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

- -

Chordoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Integrative Tumor Epidemiology Branch, National Institutes of Health

Mar 22, 2021

- -

Rhabdomyosarcoma Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Sep 01, 2020

- -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 20, 2023

- -

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: rs80359391; hg19: chr13-32912089;