rs80359659

Positions:

• chr13-32330986-TGACA-T

Variant summary

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

The NM_000059.4(BRCA2):​c.755_758delACAG​(p.Asp252fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,472 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:27
• Conservation: PhyloP100: 0.827

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 (HGNC:):

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 13-32330986-TGACA-T is Pathogenic according to our data. Variant chr13-32330986-TGACA-T is described in ClinVar as [Pathogenic]. Clinvar id is 38103.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32330986-TGACA-T is described in Lovd as [Pathogenic]. Variant chr13-32330986-TGACA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.755_758delACAG	p.Asp252fs	frameshift_variant	9/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.755_758delACAG	p.Asp252fs	frameshift_variant	9/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.386_389delACAG	p.Asp129fs	frameshift_variant	9/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.755_758delACAG		non_coding_transcript_exon_variant	8/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250934 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135640

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461338 Hom.: 0 AF XY: 0.0000220 AC XY: 16 AN XY: 726970

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:27

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
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)	Dec 21, 2012	- -
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. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM5_PTC_Strong -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 14, 2019	The p.Asp252ValfsX24 variant in BRCA2 has been reported in >60 individuals with BRCA2-related cancers and segregated with disease in at least 10 affected members of one family (Tavitigian 1996, Schrader 2016, Park 2017a, Park 2017b, Wang 2018, BIC database). Additionally, it was classified as Pathogenic on Apr. 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar Variation ID: 38103). This variant has also been identified in 0.005% (1/18384) of 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 variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 252 and leads to a premature termination codon 24 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). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Strong, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Aug 13, 2018	The c.755_758del (p.Asp252Valfs*24) variant in the BRCA2 gene is located on the exon 9 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Asp252Valfs*24), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/pancreatic cancer (PMID: 36980738, 33113089, 37024097, 24549055, 18489799, 26687385). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 38103) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (3/250934). Therefore, the c.755_758del (p.Asp252Valfs*24) variant of BRCA2 has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Asp252Valfs*24) 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 (rs80359659, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 8589730, 17636422, 18489799, 20104584, 23569316, 24549055). This variant is also known as 982del4 and 983_986del4. ClinVar contains an entry for this variant (Variation ID: 38103). 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	Jul 15, 2016	Variant summary: The c.755_758delACAG (p.Asp252Valfs) variant in BRCA2 gene is a frame shift predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population dataset of ExAC, but has been reported in multiple affected individuals and segregated with the disease in at several families (Gayther, 1999). In addition, multiple clinical diagnostic centers classify variant as Pathogenic. Taken together, the variant was classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	The BRCA2 c.755_758delACAG; p.Asp252ValfsTer24 variant (rs80359659), also known in the literature as 982del4 or 983del4, is reported in several patients with breast, ovarian or prostate cancers (Castro 2013, Machackova 2008, Tavtigian 1996). This variant is also classified as pathogenic by an expert review panel in ClinVar (Variation ID: 38103). It is found in the general population with an overall allele frequency of 0.001% (3/250934 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting four 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 Castro E et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013 May 10;31(14):1748-57. PMID: 23569316. 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. PMID: 18489799. Tavtigian SV et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996 Mar;12(3):333-7. PMID: 8589730. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2023	Observed in several individuals with BRCA2-related cancer (Tavtigian et al., 1996, Evans et al., 2008, Borg et al., 2010, Kang et al., 2015, Cao et al., 2016, Yang et al., 2017; Hu et al., 2018; Lerner-Ellis et al., 2021; Frugtniet et al., 2022); 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; Also known as 982_986del; This variant is associated with the following publications: (PMID: 25863477, 19620486, 21913181, 29566657, 30274973, 28888541, 20104584, 8589730, 17636422, 18489799, 23569316, 26852015, 24549055, 27485037, 20167696, 28205045, 28111427, 28152038, 28664506, 22762150, 21570850, 26295337, 9667259, 15131399, 25673166, 16832351, 26556299, 28724667, 30720243, 30014164, 31174498, 30309722, 31090900, 31263054, 31447099, 34399810, 32341426, 31825140, 32918181, 30787465, 31742824, 33087929, 32853339, 31892343, 33037428, 34356066, 34657373, 32885271, 29922827, 29176636) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 12, 2023	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000012 (3/250934 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in several affected individuals and families with breast and/or ovarian cancer (PMIDs: 20104584 (2010), 21570850 (2011), 24549055 (2014), 25863477 (2015), 26852015 (2016), 28205045 (2017), 29566657 (2018), 35918668 (2022)) as well as in men affected with prostate cancer (PMIDs: 23569316 (2013), 32853339 (2021)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 29, 2024	The c.755_758delACAG pathogenic mutation, located in coding exon 8 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 755 to 758, causing a translational frameshift with a predicted alternate stop codon (p.D252Vfs*24). This mutation has been described in multiple families with hereditary female and male breast cancer as well as prostate cancer (Tavtigian SV et al. Nat. Genet. 1996 Mar;12:333-7; Machackova E et al. BMC Cancer. 2008 May;8:140; Evans DG et al. Fam. Cancer. 2008 Jul;7:113-7; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57; Cao WM et al. BMC Cancer. 2015 Feb;16:64; Park B et al. Breast Cancer Res. Treat. 2017 May;163:139-150). Of note, this alteration is also designated as c.755_758del, c.755_758del4, 983del4, 983delACAG, and c.983_986del4 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	curation	Sema4, Sema4	Jan 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 11, 2023	This variant deletes 4 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.754_757delGACA, 982del4 and 983del4 in the literature. RNA analysis on carrier-derived lymphoblastoid cell lines indicates that the variant transcript is degraded by nonsense-mediated decay (PMID: 16170354). This variant has been reported in over 20 individuals and families affected with breast and ovarian cancer worldwide (PMID: 8589730, 9042907, 10359546, 12698193, 17636422, 18489799, 20104584, 22762150, 23569316, 26852015, 28205045, 29566657, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_002182) and individuals affected with prostate cancer (PMID: 23569316, 26556299) and childhood-onset leukemia (PMID: 16931905). Haplotype analysis on carrier families of European ancestry suggests a common origin (PMID: 9585613). This variant has been identified in 3/250934 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. -

Familial cancer of breast Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Center for Precision Medicine, Meizhou People's Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 03, 2024	- -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 28, 2023

- -

BRCA2-related cancer predisposition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 25, 2024

This variant deletes 4 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.754_757delGACA, 982del4 and 983del4 in the literature. RNA analysis on carrier-derived lymphoblastoid cell lines indicates that the variant transcript is degraded by nonsense-mediated decay (PMID: 16170354). This variant has been reported in over 20 individuals and families affected with breast and ovarian cancer worldwide (PMID: 8589730, 9042907, 10359546, 12698193, 17636422, 18489799, 20104584, 22762150, 23569316, 26852015, 28205045, 29566657, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_002182) and individuals affected with prostate cancer (PMID: 23569316, 26556299) and childhood-onset leukemia (PMID: 16931905). Haplotype analysis on carrier families of European ancestry suggests a common origin (PMID: 9585613). This variant has been identified in 3/250934 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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2024

The BRCA2 c.755_758delACAG variant is predicted to result in a frameshift and premature protein termination (p.Asp252Valfs*24). This variant has been reported to be causative for hereditary breast cancer (Park et al. 2017. PubMed ID: 28205045; Wang et al. 2018. PubMed ID: 29566657). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. In ClinVar, this variant is interpreted as pathogenic by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/38103/). We classify this variant as pathogenic. -

Gastric cancer Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory for Genotyping Development, RIKEN

Jul 01, 2021

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Asp252Valfs*24 variant was identified in 9 of 13606 proband chromosomes (frequency: 0.0007) from individuals or families with breast, ovarian or prostate cancer and was not identified in 6508 control chromosomes from healthy individuals (Tavtigian 1996, Evans 2008, Machackova 2008, Borg 2010, Castro 2013, Castera 2014, Cao 2016, Park 2017). The variant was also identified in the following databases: dbSNP (ID: rs80359659) as “With Pathogenic allele”, ClinVar (classified as pathogenic by ENIGMA, GeneDx, Ambry Genetics, Invitae, SCRP, and nine other submitters), Genesight-COGR, LOVD 3.0 (3x), UMD-LSDB (27x as causal), BIC Database (62x), and ARUP Laboratories (as definitely pathogenic). The variant was not identified in Cosmic, MutDB or the Zhejiang University Database. The variant was not identified in the following control databases: 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.755_758del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 252 and leads to a premature stop codon 20 codons downstream. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80359659; hg19: chr13-32905123;