rs80359316

chr13-32336283-TG-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.1929del(p.Arg645GlufsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,451,066 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:22 O:1
• Conservation: PhyloP100: 0.0100

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 13-32336283-TG-T is Pathogenic according to our data. Variant chr13-32336283-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 37769.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32336283-TG-T is described in Lovd as [Pathogenic]. Variant chr13-32336283-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1929del	p.Arg645GlufsTer15	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1929del	p.Arg645GlufsTer15	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000827 AC: 12 AN: 1451066 Hom.: 0 Cov.: 32 AF XY: 0.00000970 AC XY: 7 AN XY: 721328

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 22, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 26, 2023	- -
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	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 20, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	This variant deletes 1 nucleotide 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over a dozen individuals affected with breast and/or ovarian cancer (PMID: 9667259, 11106360, 11972384, 12672316, 16644204, 17636422, 20201734, 28008555, 29360161, 33471991; Leiden Open Variation Database DB-ID BRCA2_002150) and individuals affected with pancreatic and prostate cancer (PMID: 20201734, 20736950, 29360161). This variant also has been reported as a likely founder mutation in the UK based on haplotype analysis (PMID: 14757871). 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, 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, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -

not provided Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2022	Pathogenic founder variant in individuals of Northern European ancestry (Evans 2004, Karami 2013, Janavicius 2010); 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 2157delG; This variant is associated with the following publications: (PMID: 14757871, 26586665, 20736950, 21120943, 24312913, 28888541, 25712765, 8988179, 26041759, 12672316, 20201734, 23199084, 25085752, 27633797, 27324988, 28008555, 19471317, 29371908, 29360161, 17636422, 29084914, 32341426, 32885271, 30787465, 33087929) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2023	The BRCA2 c.1929del; p.Arg645GlufsTer15 variant (rs80359316), also known as 2157delG for traditional nomenclature, has been described in several individuals and families affected with breast and prostate cancer (Edwards 2010, Evans 2008, Gayther 1997, Lalloo 2006) and is considered a pathogenic founder variant in affected individuals of Northern European descent (Evans 2004, Janavicius 2010). This variant is reported in ClinVar (Variation ID: 37769) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant creates a frameshift by deleting a single nucleotide, 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: Edwards S et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010 Sep 7;103(6):918-24. PMID: 20736950. Evans D et al. BRCA1/2 mutation analysis in male breast cancer families from North West England. Fam Cancer. 2008;7(2):113-7. PMID: 17636422. Evans D et al. Haplotype and cancer risk analysis of two common mutations, BRCA1 4184del4 and BRCA2 2157delG, in high risk northwest England breast/ovarian families. J Med Genet. 2004 Feb;41(2):e21. PMID: 14757871. Gayther S et al. Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet. 1997 Jan;15(1):103-5. PMID: 8988179. Janavicius R et al. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA J. 2010 Sep;1(3):397-412. PMID: 23199084. Lalloo F et al. BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer. 2006 May;42(8):1143-50. PMID: 16644204. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 01, 2020	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast, ovarian, or pancreatic cancer in the published literature (PMID: 29360161 (2018), 23199084 (2010), 20736950 (2010)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 22, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2016	Variant summary: The c.1929delG (p.Arg645Glufs) variant in BRCA2 gene is a frame shift predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant has been reported in multiple affected individuals and was shown to segregate with the disease in a multiple families family. The variant is absent from the large control population dataset of ExAC. Lastly, multiple reputable databases/diagnostic centers have classified the variant of interest as Pathogenic. Taken together, the variant was 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	Apr 24, 2019	The p.Arg645GlufsX15 variant in BRCA2 has been reported in >50 individuals with BRCA2-associated cancers (Evans, 2004, Janavicius 2010, Breast Cancer Information Core (BIC) database). This variant was absent from large population 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 protein’s amino acid sequence beginning at position 645 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism for hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PS4, PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	This sequence change creates a premature translational stop signal (p.Arg645Glufs*15) 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 breast and prostate cancer (PMID: 8988179, 17636422, 20736950). It is commonly reported in individuals of Northern European ancestry (PMID: 14757871, 23199084, 24312913). This variant is also known as 2157delG. ClinVar contains an entry for this variant (Variation ID: 37769). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 22, 2023	This variant deletes 1 nucleotide 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 over a dozen individuals affected with breast and/or ovarian cancer (PMID: 9667259, 11106360, 11972384, 12672316, 16644204, 17636422, 20201734, 28008555, 29360161, 33471991; Leiden Open Variation Database DB-ID BRCA2_002150) and individuals affected with pancreatic and prostate cancer (PMID: 20201734, 20736950, 29360161). This variant also has been reported as a likely founder mutation in the UK based on haplotype analysis (PMID: 14757871). 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	Mar 22, 2022	The c.1929delG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1929, causing a translational frameshift with a predicted alternate stop codon (p.R645Efs*15). This mutation has been reported in multiple families with early-onset breast cancer, ovarian cancer, male breast cancer, pancreatic cancer, and prostate cancer (Gayther SA et al. Nat. Genet. 1997 Jan;15:103-5; Davies JF et al. J. Med. Genet. 2000 Dec;37:E42; Evans DG et al. Fam. Cancer. 2008 Jul;7:113-7; Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 02;161:575-586; Dudley B et al. Cancer. 2018 Jan). This mutation is likely a founder mutation in individuals from the northwest region of England, where it was identified in 9/660 (1.4%) families with breast/ovarian cancer (Evans DG et al. J. Med. Genet. 2004 Feb;41:e21; Janaviius R et al. EPMA J. 2010 Sep;1:397-412). Of note, this alteration is also designated as 2157delG 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. -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The BRCA2 p.Arg645GlufsX15 variant was identified in 15 of 2646 proband chromosomes (frequency: 0.006) from individuals or families with hereditary breast and ovarian cancer (Evans 2004, Frank 1998, Gayther 1997, Lalloo 2003, Lalloo 2006). In addition, two studies have reported the variant in prostate cancer patients (Castro 2013, Edwards 2010); and in one study reported it in pancreatic cancer (Showalter 2010). The variant was also identified in the following databases: dbSNP (ID: rs80359316) “With pathogenic allele”, Clinvitae database (as pathogenic by multiple submitters), ARUP Laboratories BRCA Mutations Database (as definitely pathogenic), the ClinVar database (as pathogenic by multiple submitters), the BIC database (47x with clinical importance), and UMD (35x with a “causal” classification). In addition, the variant has been reported in several papers as a founder mutation in Northwestern Britain (Evans 2004, Janavicius 2010, Karami 2013, Lalloo 2006). The variant was found to be associated with early onset hereditary breast and ovarian cancer (Lalloo 2003, Lalloo 2006). The c.1929delG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 645 and leads to a premature stop codon 15 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. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 11, 2023

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80359316; hg19: chr13-32910420;