rs80359280

Positions:

• 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_1313del​(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/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1310_1313del	p.Lys437IlefsTer22	frameshift_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1310_1313del	p.Lys437IlefsTer22	frameshift_variant	10/27	5	NM_000059.4	ENSP00000369497	A2

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:14

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 04, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
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, criteria provided, single submitter	literature only	Counsyl	Jan 28, 2015	- -
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, criteria provided, single submitter	clinical testing	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	May 27, 2024	PVS1; PM5_PTC_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 16, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	-	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 21, 2022	Criteria applied: PVS1,PS3,PS4,PM2_SUP -
Pathogenic, criteria provided, single submitter	clinical testing	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 16, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 20, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	BRCA2: PP1:Strong, PS4, PVS1:Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	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). -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 13, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	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. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Familial cancer of breast Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 05, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostics Centre, Carl Von Ossietzky University Oldenburg	Aug 21, 2023	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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 18, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2022	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. -

Breast and/or ovarian cancer Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 12, 2022

- -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

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;