rs276174853

chr13-32339466-GAATA-G

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.5116_5119del(p.Asn1706LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,586,836 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: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 1.72

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 13-32339466-GAATA-G is Pathogenic according to our data. Variant chr13-32339466-GAATA-G is described in ClinVar as [Pathogenic]. Clinvar id is 51773.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339466-GAATA-G is described in Lovd as [Pathogenic]. Variant chr13-32339466-GAATA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5116_5119del	p.Asn1706LeufsTer5	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5116_5119del	p.Asn1706LeufsTer5	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152022 Hom.: 0 Cov.: 33

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: 0.00000431 AC: 1 AN: 231774 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125546

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: 0.00000928

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434814 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 711758

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: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152022 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74258

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 14, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	The pathogenic family mutation in the BRCA2 gene (c.5116_5119delAATA) was detected in this specimen. This sequence change creates a premature translational stop signal (p.Asn1706Leufs*5) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs752413577, ExAC 0.002%). This variant has been reported in numerous individuals and families affected with breast and/or ovarian cancer (PMID: 16758124, 26026974, 22217648, 22798144, 24448499, 21990299, 23479189, 23683081). It has been described as a founder mutation in the Spanish population, and has been shown to segregate with breast cancer in several families (PMID: 19949853). This variant is also known as 5344delAATA, c.5344_5347delAATA, and c.5112_5115delAATA in the literature. ClinVar contains an entry for this variant (Variation ID: 51773) with 14 submissions and reviewed by expert panel. Lossoffunction variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic -
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, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 29, 2010	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2021	Variant summary: BRCA2 c.5116_5119delAATA (p.Asn1706LeufsX5) 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 4.3e-06 in 231774 control chromosomes. c.5116_5119delAATA 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, an expert panel (ENIGMA) and a consotrium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2023	This sequence change creates a premature translational stop signal (p.Asn1706Leufs*5) 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/or ovarian cancer (PMID: 16758124, 19949853, 21990299, 22217648, 22798144, 23479189, 23683081, 24448499, 26026974). It is commonly reported in individuals of Spanish ancestry (PMID: 19949853). This variant is also known as 5344delAATA, c.5344_5347delAATA, and c.5112_5115delAATA. ClinVar contains an entry for this variant (Variation ID: 51773). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 14, 2021	The c.5116_5119delAATA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5116 to 5119, causing a translational frameshift with a predicted alternate stop codon (p.N1706Lfs*5). This mutation has been reported in three Korean breast and/or ovarian cancer patients (Jang JH et al. J Hum Genet. 2012 Mar;57(3):212-5; Kim H et al. Breast Cancer Res. Treat., 2012 Aug;134:1315-26). This mutation has also been detected in several early onset breast/ovarian cancer families in Spain, including in a patient with male breast cancer, and has been reported to be a Castilla-Leon founder mutation (Infante M et al. J Hum Genet. 2006;51(7):611-7; Infante M et al. Breast Cancer Res Treat. 2010 Jul;122(2):567-71; Blay P et al. BMC Cancer. 2013 May 17;13:243; Beristain E et al. J Community Genet 2010 Jun; 1(2):91-9; de Juan I et al. Fam. Cancer 2015 Dec; 14(4):505-13). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this mutation is also reported as 5344_5347delAATA and 5344del4 in the 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	Dec 11, 2023	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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 16758124, 21990299, 22460208, 22486713, 22798144, 23479189, 23683081, 25863477, 26026974, 27153395, 32894085). This variant has been identified in 1/231774 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, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2013	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Nov 11, 2019

- -

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.Asn1706LeufsX5 deletion variant was identified in 10 of 2974 proband chromosomes (frequency: 0.003) from individuals or families with breast or ovarian cancer (Blay 2013, Infante 2006, Infante 2010, Jang 2012). The variant was also identified in dbSNP (ID: rs276174853) “With pathogenic allele”, HGMD, UMD (1X as a causal variant), and the BIC database (1X with clinical importance). The p.Asn1706LeufsX5 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1706 and leads to a premature stop codon 5 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)		0.0		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: rs276174853; hg19: chr13-32913603;