rs80359741

Variant names:

• chr13-32379820-TTATCA-T
• rs80359741
• NM_000059.4:c.9026_9030delATCAT

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.9026_9030delATCAT​(p.Tyr3009SerfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,516 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:20
• Conservation: PhyloP100: 7.41

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 13-32379820-TTATCA-T is Pathogenic according to our data. Variant chr13-32379820-TTATCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 38204.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379820-TTATCA-T is described in Lovd as [Pathogenic]. Variant chr13-32379820-TTATCA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9026_9030delATCAT	p.Tyr3009SerfsTer7	frameshift_variant	Exon 23 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9026_9030delATCAT	p.Tyr3009SerfsTer7	frameshift_variant	Exon 23 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8657_8661delATCAT	p.Tyr2886SerfsTer7	frameshift_variant	Exon 23 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1084_*1088delATCAT		non_coding_transcript_exon_variant	Exon 22 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*1084_*1088delATCAT		3_prime_UTR_variant	Exon 22 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250686 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135506

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460516 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726646

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:9

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

- -

Jun 30, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 30, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9026_9030del (p.Tyr3009Serfs*7) variant in the BRCA2 gene is located on the exon 23 and is predicted to result in shift of reading frame that introduces a premature translation termination codon (p.Tyr3009Serfs*7), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 29446198, 11897832, 8988179). This variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 30186769, 29084914, 25586199, 23683081, 23479189, 26026974). The variant is reported in ClinVar as pathogenic (ID: 38204) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (1/250686). Therefore, the c.9026_9030del (p.Tyr3009Serfs*7) variant of BRCA2 has been classified as pathogenic. -

Jan 01, 2017

Genologica Medica

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2021

Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Feb 08, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:5

May 05, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9026_9030del; p.Tyr3009SerfsTer7 variant (rs80359741), also known as 9245del5, is reported in the literature in numerous individuals and families affected with breast and/or ovarian cancer and has been described as a founder variant in populations of Spanish descent (Caputo 2012, de Juan Jimenez 2013, Gabaldo Barrios 2017, Solano 2018). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting five nucleotides, 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: Caputo S et al. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res. 2012 Jan;40(Database issue):D992-1002. PMID: 22144684. de Juan Jiménez I et al. Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence. Fam Cancer. 2013 Dec;12(4):767-77. PMID: 23479189. Gabaldó Barrios X et al. Molecular characterization and clinical interpretation of BRCA1/BRCA2 variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical-pathological features in BRCA carriers and non-carriers. Fam Cancer. 2017 Oct;16(4):477-489. PMID: 28477318. Solano AR et al. BRCA1 and BRCA2 Mutations Other Than the Founder Alleles Among Ashkenazi Jewish in the Population of Argentina. Front Oncol. 2018 Aug 21;8:323. PMID: 30186769. -

Mar 05, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9026_9030del (p.Tyr3009Serfs*7) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in ZZZZ The frequency of this variant in the general population, 0.000029 (1/34538 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Nov 02, 2021

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; Identified in several hereditary breast/ovarian cancer families and has been reported as a founder variant in Northern Spanish populations (Tavtigian 1996, Janaviius 2010, Caputo 2012, de Juan Jimenez 2013, Labidi-Galy 2018, Solano 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9254del5; This variant is associated with the following publications: (PMID: 22632462, 21735045, 24123850, 23479189, 22144684, 8589730, 20033483, 12655574, 18176857, 23683081, 28477318, 29084914, 30720243, 30122538, 30186769, 23199084, 30969264, 26295337, 26026974, 25586199, 32854451, 32039725, 29625052) -

Hereditary cancer-predisposing syndrome Pathogenic:2

May 18, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9026_9030delATCAT pathogenic mutation, located in coding exon 22 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 9026 to 9030, causing a translational frameshift with a predicted alternate stop codon (p.Y3009Sfs*7). This pathogenic mutation has been identified in multiple breast and/or ovarian cancer families to date (Tavtigian SV et al. Nat. Genet. 1996 Mar;12:333-7; Caputo S et al. Nucleic Acids Res. 2012 Jan;40:D992-1002; Blay P et al. BMC Cancer 2013 May;13:243; de Juan I et al. Fam. Cancer 2015 Dec;14:505-13; Gabaldó Barrios X et al. Fam. Cancer 2017 Oct;16(4):477-489), and has been described as a founder mutation of Northeast Spanish origin (de Juan Jiménez I et al. Fam. Cancer 2013 Dec;12:767-77). 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. -

Jun 26, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 5 nucleotides in exon 23 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 more than 30 individuals with a personal or family history of breast and/or ovarian cancer and is a recurrent mutation in the Spanish population (PMID: 12655567, 12655574, 12955716, 17262179, 23479189, 23683081, 25586199, 26026974, 28477318, 29084914). This variant has been identified in 1/250686 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Jul 22, 2024

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.Tyr3009Serfs*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 present in population databases (rs80359741, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8589730, 12655574, 22632462, 23479189, 25586199, 26026974). It is commonly reported in individuals of Spanish ancestry (PMID: 8589730, 12655574, 22632462, 23479189, 25586199, 26026974). This variant is also known as 9254del5. ClinVar contains an entry for this variant (Variation ID: 38204). For these reasons, this variant has been classified as Pathogenic. -

Mar 12, 2018

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.9026_9030delATCAT (p.Tyr3009SerfsX7) 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 (eg. c.9076C>T, p.Gln3026X; c.9093_9094delinsG, p.Thr3033fsX29; c.9097dupA, p.Thr3033fsX11). The variant allele was found at a frequency of 4.1e-06 in 245684 control chromosomes (gnomAD and literature). c.9026_9030delATCAT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Serova-Sinilnikova_1997, Neuhausen_1998, Campos_2003, Beristain_2007, Labidi-Galy_2017). 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. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Nov 02, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:1

May 28, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs80359741; hg19: chr13-32953957;