rs80359412

Positions:

• chr13-32338216-TAATA-T

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.3865_3868delAAAT​(p.Lys1289fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,389,974 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: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: 0.878

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 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 13-32338216-TAATA-T is Pathogenic according to our data. Variant chr13-32338216-TAATA-T is described in ClinVar as [Pathogenic]. Clinvar id is 37862.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338216-TAATA-T is described in Lovd as [Pathogenic]. Variant chr13-32338216-TAATA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.3865_3868delAAAT	p.Lys1289fs	frameshift_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.3865_3868delAAAT	p.Lys1289fs	frameshift_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.3496_3499delAAAT	p.Lys1166fs	frameshift_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.3865_3868delAAAT		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1389974 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 687302

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: 9.31e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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)	Mar 27, 2008	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This is a deletion of four base pairs causing a frameshift at codon 1289. This creates a novel stop codon 3 amino acid residues later and is expected to result in a truncated, non-functional protein. Truncating variants in BRCA2 are known to be pathogenic. This variant is also known as 4093delAAAT or 4093del4 in the literature and it has been reported in patients with familiar breast/ovarian cancer (PMID: 11102978, 22729890, 20104584). The mutation database ClinVar contains entries for this variant (Variation ID: 37862). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2016	Variant summary: The c.3865_3868delAAAT (p.Lys1289Alafs) variant in the BRCA2 gene is a frameshift change predicted to cause a loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay, which is a known disease mechanism in HBOC. The variant has been reported in multiple affected individuals and is absent from the large control population dataset of EXAC. The results of the functional study have shown that patient-derived lymphocytes carrying this variant exhibit increased chromosomal radiosensitivity in metaphase-based radiation assay, confirming deleterious outcome for this variant (Becker_2012). Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change creates a premature translational stop signal (p.Lys1289Alafs*3) 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 familial breast and ovarian cancer (PMID: 11102978, 20104584, 22729890). This variant is also known as 4093delAAAT or 4093del4. ClinVar contains an entry for this variant (Variation ID: 37862). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects BRCA2 function (PMID: 22729890). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 13, 2020	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in multiple individuals with hereditary breast and ovarian cancer in the published literature (PMID: 29797126 (2018), 24728189 (2014), 24578176 (2014), 22729890 (2012), 20104584 (2010), 11802209 (2002), 11102978 (2000)) and functional data indicates that this variant is damaging in a metaphase-based radiation assay (PMID: 22729890 (2012)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2021	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 in large population cohorts (Lek 2016) Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database This variant is associated with the following publications: (PMID: 32832836, 30093976, 28993434, 24578176, 22762150, 24065114, 22729890, 20104584, 26187060, 24728189, 11102978, 11802209, 29446198, 32072338) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 07, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Jan 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 14, 2022	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 four individuals affected with breast or ovarian cancer and also in two unaffected individuals (PMID: 20104584, 24728189, 28993434, 29797126, 33471991; Leiden Open Variation Database DB-ID BRCA2_001167). 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	Feb 07, 2022	The c.3865_3868delAAAT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 3865 to 3868, causing a translational frameshift with a predicted alternate stop codon (p.K1289Afs*3). This mutation has been reported in multple breast and/or ovarian cancer patients of varying ethnicities (Shiri-Sverdlov R et al. Hum. Mutat. 2000 Dec;16:491-501; Phelan CM et al. Hum Mutat, 2002 Nov;20:352-7; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Becker AA et al. Breast Cancer Res. Treat. 2012 Aug;135:167-75; Kang PC et al. Breast Cancer Res. Treat. 2014 Apr;144:635-42; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Wen WX et al. J. Med. Genet. 2018 Feb;55:97-103; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; hen L et al. Breast Cancer Res Treat, 2020 Apr;180:759-766). This mutation was also identified in a cohort of 3579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). Of note, this alteration is also designated as 4093del4 and 4093delAAAT 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. -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 20, 2024	- -
Pathogenic, no assertion criteria provided	literature only	Center for Precision Medicine, Meizhou People's Hospital	-	- -

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: rs80359412; hg19: chr13-32912353;