rs80359280

Variant names:

• chr13-32332778-AAAAG-A
• rs80359277
• NM_000059.4:c.1310_1313delAAGA

Your query was ambiguous. Multiple possible variants found:

• chr13-32332778-AAAAG-A
• chr13-32332778-A-AAAAG
• chr13-32332778-AAAAGAAAG-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.1310_1313delAAGA​(p.Lys437IlefsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000809 in 1,607,776 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 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:36
• 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32332778-AAAAG-A is Pathogenic according to our data. Variant chr13-32332778-AAAAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 37737.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332778-AAAAG-A is described in Lovd as [Pathogenic]. Variant chr13-32332778-AAAAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1310_1313delAAGA	p.Lys437IlefsTer22	frameshift_variant	Exon 10 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1310_1313delAAGA	p.Lys437IlefsTer22	frameshift_variant	Exon 10 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.941_944delAAGA	p.Lys314IlefsTer22	frameshift_variant	Exon 10 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1310_1313delAAGA		non_coding_transcript_exon_variant	Exon 9 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243408 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131926

Gnomad AFR exome AF: 0.0000643

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1455552 Hom.: 0 AF XY: 0.00000829 AC XY: 6 AN XY: 723992

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000340

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:36

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:13

Oct 04, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2017

Genologica Medica

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1; PM5_PTC_Strong -

Jan 28, 2015

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 22, 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. -

Aug 26, 2022

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS3,PS4,PM2_SUP -

-

University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:11

Dec 06, 2022

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 the heterozygous state individuals with breast and/or ovarian cancer (Gayther et al., 1997; Zhang et al., 2011; Caputo et al., 2012; Kang et al., 2015; Laarabi et al., 2017); 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 1310del4, 1537del4, or 1538del4; This variant is associated with the following publications: (PMID: 25863477, 26219728, 27446417, 27469594, 26360800, 28324225, 26295337, 20683152, 12655567, 22798144, 30263132, 28918466, 29752822, 29922827, 28888541, 29884136, 32040686, 21324516, 8988179, 19478387, 26843898, 12955716, 22144684, 22684231, 15131399, 2290898, 28776284, 28577564, 28263838, 28814288, 28127413, 22217648, 18465347, 19471317, 27025497, 28724667, 30720863, 28111427, 30720243, 30702160, 30322717, 30535581, 31090900, 31447099, 31263054, 33240314, 33468216, 34456966, 30787465, 34645131, 32778078, 34150972, 34490083, 34646395, 33606809, 34247626, 32596633, 31060517, 23519070, 25418591, 32341426, 31825140, 31209999, 30675319, 31327751, 30352249, 29681614, 29791287, 33726785, 33646313, 32719484, 33087929, 20104584, 25381700) -

Feb 17, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change deletes four nucleotides from exon 10 of the BRCA2 mRNA (c.1310_1313delAAGA), causing a frameshift after codon 437 and the creation of a premature translational stop signal 22 amino acid residues later p.(Lys437Ilefs*22). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular variant, also known as BRCA2 1310del4, 1537del4 and 1538del4 using alternate nomenclature has been described in the literature in heterozygous state in numerous individuals and families affected by breast and/or ovarian cancer (PMID: 8988179, 12955716, 25863477). This variant has also been described in homozygous state in a child affected by Fanconi Anaemia (PMID: 25381700). The mutation database ClinVar contains entries for this variant (Variation ID: 37737). -

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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 23, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 16, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: PP1:Strong, PS4, PVS1:Strong -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 20, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 01, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA2 c.1310_1313delAAGA (p.Lys437Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g.c.1456C>T (p.Gln486X) and c.1654delT (p.Ser552fs)). This variant was found in 1/120430 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in multiple HBOC patients. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Jan 23, 2025

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.Lys437Ilefs*22) 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 (rs80359277, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8988179, 12955716, 18465347, 20683152, 22144684, 25863477). This variant is also known as 1538del4 and 1529del4. ClinVar contains an entry for this variant (Variation ID: 37737). For these reasons, this variant has been classified as Pathogenic. -

Feb 13, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys437IlefsX22 variant in BRCA2 has been reported in the heterozygous state in >30 individuals with BRCA2-associated cancers (Gayther 1997 PMID: 8988179, Caputo 2012 PMID: 22144684, Laarabi 2017 PMID: 28577564, BIC database: https://research.nhgri.nih.gov/bic/) and in the homozygous state in a child with Fanconi anemia (Malric 2015 PMID: 25381700). This variant has also been identified in 0.009% (1/10618) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. The p.Lys437IlefsX22 variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 437 and leads to a premature termination codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in HBOC. Additionally, this variant was classified as pathogenic on Apr. 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar Variation ID: 37737). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PM2_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Mar 29, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 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 over 20 heterozygous individuals affected with breast or ovarian cancer (PMID: 17100994, 21156238, 21324516, 22144684, 22739995, 22798144, 22921157, 23479189, 24156927, 24549055, 25007954, 25777348, 20683152, 26843898, 30322717, 34645131, 33471991, 34490083) and has been identified in 110 families among the CIMBA participants (PMID: 29446198). This variant has also been observed in a homozygous state in 2 individuals affected with Fanconi Anemia and in a compound heterozygous state with a known pathogenic BRCA2 variant in 1 individual affected with Fanconi Anemia (PMID: 16015582, 25381700). This variant has been identified in 1/243408 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. -

Mar 18, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1310_1313delAAGA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1310 to 1313, causing a translational frameshift with a predicted alternate stop codon (p.K437Ifs*22). This mutation has been detected in numerous European, Asian, and African breast/ovarian cohorts to date and has been described as a founder in several populations (Diez O et al. Hum. Mutat. 2003 Oct;22:301-12; Thomassen M et al. Acta Oncol. 2008;47:772-7; Cherbal F et al. Dis. Markers. 2010;28:377-84; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Caputo S et al. Nucleic Acids Res. 2012 Jan;40:D992-1002; Jang JH et al. J. Hum. Genet. 2012 Mar;57:212-5; Wojcik P et al. Hered. Cancer Clin. Pract. 2016 Feb;14:5; Jouali F et al. Oncol. Lett. 2016 Aug;12:1192-1196; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Laarabi FZ et al. BMC Res Notes. 2017 Jun;10:188; Li JY et al. Int. J. Cancer. 2019 Jan;144(2):281-289). It has also been identified in individuals with Fanconi anemia (Malric A et al. Pediatr. Blood Cancer. 2015 Mar;62(3):463-70). Of note, this alteration is also designated as c.1301_1304del4, 1310del4, 1538del4, 1538_1541del4, and 1538_1541delAAGA 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 classified as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -

Familial cancer of breast Pathogenic:2

Mar 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2023

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The variant BRCA2:c.1310_1313delAAGA, p.(Lys437Ilefs), which is located in the coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 1310 - 1313 which is suggested to cause a frameshifth. The lysine at protein position 437 is replaced by isoleucine and is followed by a premature stop codon after 22 additional amino acids. The premature stop codon is predicted to cause non-sense mediated decay and a truncated or absent of the gene product. The variant is classified as very rare with an allele frequency on the overall population= 0.000033 (gnomAD V3.1.2). The variant has already detected in numerous breast cancer/ovarian cancer affected individuals (PMID: 20104584, 28577564, 33726785, 26843898) and was including as a founder mutation in several populations (PMID: 12955716, 18465347, 22144684, 22217648). There are 30 entries for this variant as pathogenic in ClinVar (VCV000037737.57). The variant is classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Jan 12, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition Pathogenic:1

Sep 06, 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 4 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 over 20 heterozygous individuals affected with breast or ovarian cancer (PMID: 17100994, 21156238, 21324516, 22144684, 22739995, 22798144, 22921157, 23479189, 24156927, 24549055, 25007954, 25777348, 20683152, 26843898, 30322717, 34645131, 33471991, 34490083) and has been identified in 110 families among the CIMBA participants (PMID: 29446198). This variant has also been observed in a homozygous state in 2 individuals affected with Fanconi Anemia and in a compound heterozygous state with a known pathogenic BRCA2 variant in 1 individual affected with Fanconi Anemia (PMID: 16015582, 25381700). This variant has been identified in 1/243408 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. -

Malignant tumor of breast Pathogenic:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Lys437IlefsX22 deletion variant has been reported in the literature in 2/3156 proband chromosomes of individuals with hereditary breast and/or ovarian cancer (HBOC). However, no control chromosomes were evaluated (Caux-Moncoutier_2009, Caux-Moncoutier_2011). The variant was also identified in the UMD database (34x) as "causal" and in the BIC database (10x) as having "clinical importance". This deletion is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 437 and leads to a premature stop codon 22 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants in the BRCA2 gene are an established disease mechanism in hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. -

Ovarian neoplasm Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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: rs80359277; hg19: chr13-32906915;