rs80359496

Positions:

• chr13-32339571-ATTTAAGT-A

Variant summary

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

The NM_000059.4(BRCA2):​c.5217_5223del​(p.Tyr1739Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,457,104 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. Y1739Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:22
• Conservation: PhyloP100: 1.73

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 13-32339571-ATTTAAGT-A is Pathogenic according to our data. Variant chr13-32339571-ATTTAAGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 51822.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339571-ATTTAAGT-A is described in Lovd as [Pathogenic]. Variant chr13-32339571-ATTTAAGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.5217_5223del	p.Tyr1739Ter	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.5217_5223del	p.Tyr1739Ter	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248722 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134578

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1457104 Hom.: 0 AF XY: 0.00000414 AC XY: 3 AN XY: 724960

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: 0.00000812

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	Jul 01, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 06, 2013	- -
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, 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	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The c.5217_5223del (p.Tyr1739X) deletion variant has been previously reported in the literature in one of 386 probands with breast carcinoma (Malone 2000). The variant was also reported 14 times in BIC database as having "clinical importance". Several databases including LOVD and UMD also report different variants at the same codon with the same amino acid consequence. This deletion is predicted to cause a frameshift, which leads to a premature stop codon at position 1739. 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 for hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Apr 27, 2018	This c.5217_5223del (p.Tyr1739*) variant in exon 11 of the BRCA2 gene is a deletion of seven nucleotides and is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. This particular variant (also published as c.5445del7) has been reported in multiple hereditary breast and ovarian cancer patients (PMID: 10717622, 26350514). The c.5217_5223del variant in the BRCA2 gene is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2020	The BRCA2 c.5217_5223del; p.Tyr1739Ter variant (rs80359496), also known as 5445del7, is reported in the literature in multiple families affected with breast and ovarian cancer syndrome (Malone 2000, Scottish/Northern Irish BRCAI/BRCA2 Consortium 2003). This variant is found on only a single chromosome in the Genome Aggregation Database (1/248722 alleles), indicating it is not a common polymorphism. This variant deletes seven nucleotides and induces an early termination codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, this variant is considered pathogenic. References: Malone KE et al. Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer. 2000 Mar 15;88(6):1393-402. Scottish/Northern Irish BRCAI/BRCA2 Consortium. BRCA1 and BRCA2 mutations in Scotland and Northern Ireland. Br J Cancer. 2003 Apr 22;88(8):1256-62. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 15, 2022	PP5, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 03, 2022	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, 0.000004 (1/248722 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 12698193 (2003), 10717622 (2000), 22776961 (2012)) and ovarian cancer (PMID: 26350514 (2015)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2023	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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 10717622, 22776961, 26350514, 28888541, 29339979); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 5445del7; This variant is associated with the following publications: (PMID: 12649099, 26320393, 23242139, 16086312, 10717622, 15131399, 26295337, 26350514, 15993273, 28152038, 22776961, 29339979, 12698193, 29371908, 30720243, 30787465, 31892343, 31447099, 28888541, 35969835, 36623239) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 02, 2022	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

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 28, 2024	This sequence change creates a premature translational stop signal (p.Tyr1739*) 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 (rs80359496, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 10717622, 26350514). This variant is also known as 5445del7. ClinVar contains an entry for this variant (Variation ID: 51822). 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	Apr 24, 2021	Variant summary: BRCA2 c.5217_5223delTTTAAGT (p.Tyr1739X) 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 4e-06 in 250156 control chromosomes. c.5217_5223delTTTAAGT 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 consortium (CIMBA) 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. -

BRCA2-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This frameshifting variant in exon 11 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and ovarian cancer (PMID: 10717622, 28888541, 29339979, 30787465, 30720243, 31447099). Loss-of-function variation at the same amino acid residue (p.Tyr1739) has been previously reported in individuals with breast, ovarian, and prostate cancer (PMID: 12872265, 26681312, 32341426, 9150154, 11802209). Loss-of-function variation in BRCA2 is an established mechanism of disease (PMID: 20104584, 20301425). The c.5217_5223del (p.Tyr1739Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/248722) and thus is presumed to be rare. Based on the available evidence, the c.5217_5223del (p.Tyr1739Ter) variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 01, 2024	The BRCA2 c.5217_5223del7 variant is predicted to result in premature protein termination (p.Tyr1739*). This frameshift variant results in a premature termination codon, a nonsense change. This variant has been reported in individual(s) with breast cancer and ovarian cancer (Malone et al 2000. PubMed ID: 10717622; Høberg-Vetti H et al 2015. PubMed ID: 26350514). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51822/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 13, 2023	This variant deletes 7 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 observed in at least six individuals affected with breast and/or ovarian cancer and 2 unaffected individuals, and in suspected hereditary breast and ovarian cancer families (PMID: 10717622, 11710890, 12698193, 21702907, 22776961, 26350514, 33471991; Leiden Open Variation Database DB-ID BRCA2_003626). This variant has been identified in 1/248722 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	Feb 15, 2023	The c.5217_5223delTTTAAGT (p.Y1739*) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of 7 nucleotides from position 5217 to 5223. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 1739. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/248722) total alleles studied. The highest observed frequency was 0.001% (1/112616) of European (non-Finnish) alleles. This mutation was reported in a woman affected with breast carcinoma (Malone, 2000) and in another family with hereditary breast and ovarian cancer syndrome (Lubinski, 2004). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in 61 families (Heramb, 2018). Of note, this alteration is also designated as 5445del7 in older published literature. Based on the available evidence, this alteration is classified as pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 23, 2023

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80359496; hg19: chr13-32913708;