Submissions for variant NM_000059.4(BRCA2):c.1310_1313del (p.Lys437fs)

dbSNP: rs80359277

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031318	SCV000282355	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203644	SCV000071792	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	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.
Ambry Genetics	RCV000131062	SCV000185992	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-18	criteria provided, single submitter	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.
GeneDx	RCV000043779	SCV000210713	pathogenic	not provided	2022-12-06	criteria provided, single submitter	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)
Counsyl	RCV000031318	SCV000221095	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-01-28	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000043779	SCV000224771	pathogenic	not provided	2014-12-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000043779	SCV000296609	pathogenic	not provided	2020-03-20	criteria provided, single submitter	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031318	SCV000326537	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000031318	SCV000577946	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131062	SCV000688704	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-29	criteria provided, single submitter	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.
GeneKor MSA	RCV000043779	SCV000693556	pathogenic	not provided	2020-01-01	criteria provided, single submitter	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000203644	SCV000694532	pathogenic	Hereditary breast ovarian cancer syndrome	2017-05-01	criteria provided, single submitter	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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031318	SCV000744407	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000043779	SCV001449774	pathogenic	not provided	2014-06-16	criteria provided, single submitter	clinical testing
Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	RCV000031318	SCV001519675	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000043779	SCV002010736	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000043779	SCV002016820	pathogenic	not provided	2023-02-17	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798038	SCV002042431	pathogenic	Breast and/or ovarian cancer	2022-01-12	criteria provided, single submitter	clinical testing
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	RCV000031318	SCV002104286	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000043779	SCV002585441	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	BRCA2: PP1:Strong, PS4, PVS1:Strong
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000043779	SCV002761142	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003445092	SCV004213652	pathogenic	Familial cancer of breast	2024-03-05	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031318	SCV004812133	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-03-21	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS3,PS4,PM2_SUP
All of Us Research Program, National Institutes of Health	RCV004803001	SCV004846899	pathogenic	BRCA2-related cancer predisposition	2024-09-06	criteria provided, single submitter	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000203644	SCV004848270	pathogenic	Hereditary breast ovarian cancer syndrome	2022-02-13	criteria provided, single submitter	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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031318	SCV005045978	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Sharing Clinical Reports Project (SCRP)	RCV000031318	SCV000053923	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-10-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031318	SCV000145851	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000203644	SCV000587590	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353721	SCV000591735	pathogenic	Malignant tumor of breast		no assertion criteria provided	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031318	SCV000733227	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785565	SCV000924137	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000043779	SCV001906111	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000043779	SCV002036327	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031318	SCV002588852	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Diagnostics Centre, Carl Von Ossietzky University Oldenburg	RCV003445092	SCV004174187	pathogenic	Familial cancer of breast	2023-08-21	no assertion criteria provided	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.