rs80359302

chr13-32333228-AAAAAG-A

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.1755_1759del(p.Lys585AsnfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,460,752 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. K584K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:20 U:1 O:1
• Conservation: PhyloP100: 3.80

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 13-32333228-AAAAAG-A is Pathogenic according to our data. Variant chr13-32333228-AAAAAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 37754.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32333228-AAAAAG-A is described in Lovd as [Pathogenic]. Variant chr13-32333228-AAAAAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1755_1759del	p.Lys585AsnfsTer3	frameshift_variant	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1755_1759del	p.Lys585AsnfsTer3	frameshift_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250222 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135364

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460752 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 726652

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	This variant deletes 5 nucleotides in exon 10 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 individuals affected with breast, ovarian, or pancreatic cancer (PMID: 16284991, 17301269, 19620486, 20616022, 251866, 26681312, 29446198) and has been identified in 14 families among the CIMBA participants (PMID: 29446198; https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 1/250222 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, 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)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 12, 2022	The BRCA2 c.1755_1759del (p.Lys585AsnfsTer3) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant has been reported in individuals with breast cancer (PMID: 22009639) and ovarian cancer (PMID: 28888541, 30309722), as well as in individuals with other cancer types including fallopian tube and pancreatic (PMID: 22009639, 30787465). It has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is also known as 1983del5 in the literature. In summary, this variant meets criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Apr 09, 2020	This variant deletes five nucleotides causing a frameshift at position 585 which leads to a premature stop codon. This variant is predicted to result in a loss of protein function, which is a well-established mechanism of disease for the BRCA2 gene (Borg 2010). In the literature, this variant has been reported in individuals with breast, ovarian, and pancreatic cancers (Pal 2005, Susswein 2016, Tung 2015, Watson 2009). This variant has been observed one time in the gnomAD database (https://gnomad.broadinstitute.org/). Based on this information, we consider this variant to be pathogenic. PM2; PVS1 -
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 12, 2011	- -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 08, 2021	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been identified in individuals with breast and/or ovarian cancer in the published literature (PMID: 26681312 (2015), 25186627 (2015), 22009639 (2012), 15131399 (2004)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2023	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; Observed in individuals with personal or family history of BRCA2-associated cancers (Lubinski et al., 2004; Pal et al., 2005; Couch et al., 2007; Watson et al., 2009; Senter et al., 2014); Not observed 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 1983del5 or 1983_1987delGAAAA; This variant is associated with the following publications: (PMID: 17301269, 19941162, 27165126, 26681312, 30720243, 28888541, 15131399, 22009639, 19620486, 16284991, 20616022, 23725378, 30309722, 31447099, 31892343, 33504652, 30787465) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 30, 2022	PP5, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 20, 2021	The BRCA2 c.1755_1759delGAAAA, p.Lys585AsnfsTer3 variant (rs80359302) has been reported in a family with breast and/or ovarian cancer (Lubinski 2004). This variant is reported in ClinVar (Variation ID: 37754), and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, the variant is classified as pathogenic. References: Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	This sequence change creates a premature translational stop signal (p.Lys585Asnfs*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 present in population databases (rs80359302, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer and breast, pancreatic, and fallopian tube cancer (PMID: 15131399, 16284991, 19620486, 20616022, 25186627, 26681312). This variant is also known as 1983del5. ClinVar contains an entry for this variant (Variation ID: 37754). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2022	Variant summary: BRCA2 c.1755_1759delGAAAA (p.Lys585AsnfsX3) 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 250222 control chromosomes. c.1755_1759delGAAAA has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer, fallopian tube cancer and pancreatic cancer (Susswein_2016, Senter_2014, Pal_2005, Lubinski_2004). These data indicate that the variant is very likely to be associated with disease. 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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 20, 2023	This variant deletes 5 nucleotides in exon 10 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 individuals affected with breast, ovarian, or pancreatic cancer (PMID: 16284991, 17301269, 19620486, 20616022, 251866, 26681312, 2729446198) and has been identified in 14 families among the CIMBA participants (PMID: 29446198; https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 1/250222 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	Apr 29, 2022	The c.1755_1759delGAAAA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 1755 to 1759, causing a translational frameshift with a predicted alternate stop codon (p.K585Nfs*3). This mutation has been reported in multiple breast and/or ovarian cancer families to date (Lubinski J et al. Fam. Cancer. 2004;3:1-10; Watson P et al. J. Clin. Oncol. 2009 Aug;27:3894-900; Tung N et al. Cancer. 2015 Jan;121:25-33). This alteration has also been reported in one high risk pancreatic cancer family (Couch FJ et al. Cancer Epidemiol. Biomarkers Prev. 2007 Feb;16:342-6). Of note, this mutation is also designated as 1983del5 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. -

BRCA2-related disorder Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 18, 2018	The BRCA2 c.1755_1759delGAAAA (p.Lys585AsnfsTer3) variant, also known as 1983del5 results in a frameshift and is predicted to result in premature termination of the protein. The p.Lys585AsnfsTer3 variant has been reported in at least three studies in which it is found in a heterozygous state in a total of eight patients diagnosed with breast, ovarian/fallopian tube, pancreatic, or other cancers (Lubinski et al. 2004; Pal et al. 2005; Susswein et al. 2016). The p.Lys585AsnfsTer3 variant is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database though this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Hall et al. (2016) developed a mouse model of pancreatic acinar cell carcinoma and determined that it was homozygous for the BRCA2 p.Lys585AsnfsTer3 variant. Immunohistochemical staining of tissues from this mouse model revealed that the mutated BRCA2 protein was not localized to the nucleus, but was instead only expressed in the cytoplasm, as compared to normal tissues where BRCA2 was localized to both the nucleus and cytoplasm. This variant has not been reported in the literature in association with Fanconi anemia, and this variant could not be ruled out of causing this disease based on based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode. Due to the potential impact of frameshift variants, the p.Lys585AsnfsTer3 variant is classified as pathogenic for BRCA2-related disorders. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 03-09-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 02, 2022

- -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 21, 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: rs80359302; hg19: chr13-32907365;