13-32339699-CA-C

Variant names:

• chr13-32339699-CA-C
• rs80359507
• NM_000059.4:c.5351delA

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.5351delA​(p.Asn1784ThrfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: -0.0180

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 13-32339699-CA-C is Pathogenic according to our data. Variant chr13-32339699-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 37961.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339699-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32339699-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32339699-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32339699-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5351delA	p.Asn1784ThrfsTer7	frameshift_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5351delA	p.Asn1784ThrfsTer7	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4982delA	p.Asn1661ThrfsTer7	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5351delA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460670 Hom.: 0 Cov.: 45 AF XY: 0.00 AC XY: 0 AN XY: 726670

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

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

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

Variant allele predicted to encode a truncated non-functional protein. -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 13, 1997

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 30, 2022

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG codes:PVS1_VeryStrong, PS4_Moderate, PM2_Moderate -

Mar 18, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:5

Apr 19, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 07, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.5351delA; p.Asn1784ThrfsTer7 variant (rs80359507), also known as c.5573delA/c.5579delA, is reported in the literature in individuals affected with prostate cancer (Roed Nielsen 2016), ovarian cancer (Gayther 1997, Chan 2018), and HBOC syndrome (Palmero, 2018, Ow 2019). This variant is also reported in ClinVar (Variation ID: 37961) and interpreted by the expert panel ENIGMA as pathogenic (Spurdle 2012). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes 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 to be pathogenic. References: Chan et al. Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers. Oncotarget. 2018 Jul 17;9(55):30649-30660. PMID: 30093976. Gayther SA 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. Ow SGW et al. PLoS One. 2019 Mar 15;14(3):e0213746. PMID: 30875412. Palmero EI et al. The germline mutational landscape of BRCA1 and BRCA2 in Brazil. Sci Rep. 2018 Jun 15;8(1):9188. PMID: 29907814. Roed Nielsen H et al. Increased risk of male cancer and identification of a potential prostate cancer cluster region in BRCA2. Acta Oncol. 2016;55(1):38-44. PMID: 26360800. Spurdle AB et al. ENIGMA--evidence-based network for the interpretation of germline mutant alleles: an international initiative to evaluate risk and clinical significance associated with sequence variation in BRCA1 and BRCA2 genes. Hum Mutat. 2012 Jan;33(1):2-7. PMID: 21990146. -

May 28, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with breast or ovarian cancer in the published literature ((PMID: 29907814 (2018), 30093976 (2018), 25863477 (2015), 25682074 (2015), 22798144 (2012), 10486320 (1999), 8988179 (1997)). Based on the available information, this variant is classified as pathogenic. -

Aug 29, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 a personal or family history consistent with pathogenic variants in this gene (Gayther et al., 1997; Pages et al., 2001; Thomassen et al., 2008; Kang et al., 2015; Roed Nielsen et al., 2016); 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 5579delA; This variant is associated with the following publications: (PMID: 24612714, 18465347, 26187060, 8988179, 22798144, 25863477, 26360800, 11207042, 23415752, 17688236, 25682074, 29907814, 10486320, 22923021, 29446198, 30093976, 30875412, 30787465, 34645131) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

May 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 detected in at least 3 individuals affected with breast and/or ovarian cancer (PMID: 22798144, 25682074, 25863477, 33471991; Leiden Open Variation Database DB-ID BRCA2_002881), one individual affected with prostate cancer (PMID: 26360800) and several hereditary breast and ovarian cancer families (PMID: 8988179, 11207042, 18465347, 29383094, 29907814). 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. -

Apr 15, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5351delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 5351, causing a translational frameshift with a predicted alternate stop codon (p.N1784Tfs*7). This mutation has been reported in an ovarian cancer family (Gayther SA et al. Nat. Genet. 1997 Jan;15:103-5) and in Korean individuals with personal and/or family histories of breast cancer (Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26). In a Danish cohort of 290 families with male BRCA1/2 mutation carriers, this mutation was identified in two relatives both affected with prostate cancer in their 70s (Roed Nielsen H et al. Acta Oncol 2016 Sep;55:38-44). Of note, this alteration is also designated as 5573delA and 5579delA 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Nov 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn1784Thrfs*7) 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, ovarian, and prostate cancer (PMID: 8988179, 22923021, 25863477, 26360800). This variant is also known as 5573delA, 5579delA and c.5351insA (p.Asn1784Lysfs*3). ClinVar contains an entry for this variant (Variation ID: 37961). For these reasons, this variant has been classified as Pathogenic. -

Mar 28, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.5351delA (p.Asn1784ThrfsX7) 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 was absent in 250394 control chromosomes. c.5351delA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Gayther_1997, Thomassen_2008, Kang_2015, Wong-Brown_2015). 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 cancer predisposition Pathogenic:1

Jul 29, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 detected in at least 3 individuals affected with breast and/or ovarian cancer (PMID: 22798144, 25682074, 25863477, 33471991; Leiden Open Variation Database DB-ID BRCA2_002881), one individual affected with prostate cancer (PMID: 26360800) and several hereditary breast and ovarian cancer families (PMID: 8988179, 11207042, 18465347, 29383094, 29907814). 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. -

Familial cancer of breast Pathogenic:1

Feb 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs80359507; hg19: chr13-32913836;