Submissions for variant NM_000059.4(BRCA2):c.7069_7070del (p.Leu2357fs)

dbSNP: rs80359636

Total submissions: 41

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031664	SCV000282439	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	RCV000195404	SCV000073149	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu2357Valfs*2) 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 (rs756538291, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 9429140, 21324516, 24504028, 24728189). This variant is also known as 7297delCT. ClinVar contains an entry for this variant (Variation ID: 38082). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131032	SCV000185962	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-18	criteria provided, single submitter	clinical testing	The c.7069_7070delCT pathogenic mutation, located in coding exon 13 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 7069 to 7070, causing a translational frameshift with a predicted alternate stop codon (p.L2357Vfs*2). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) cohorts (Garvin AM et al. J. Med. Genet. 1997 Dec;34:990-5; Thomassen M et al. Acta Oncol. 2008;47:772-7; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Litton JK et al. Cancer. 2012 Jan;118:321-5; Chong HK et al. PLoS ONE, 2014 May;9:e97408; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24:326-333; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13). This mutation has also been reported in prostate and pancreatic cancer cohorts (Schwartz M et al. Clin Genet, 2019 12;96:579-584; Boyle JL et al. JCO Precis Oncol, 2020 Mar;4; Moses M et al. Oncotarget, 2020 Jan;11:15-21). Of note, this alteration is also designated as 7297delCT 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.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031664	SCV000196001	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000045136	SCV000210786	pathogenic	not provided	2020-03-04	criteria provided, single submitter	clinical testing	Observed in multiple individuals with BRCA2-related cancers (Garvin 1997, Zhang 2011, Cunningham 2014, Song 2014, Ellingson 2015, Decker 2016, Afghahi 2017); 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26745875, 24728189, 26681312, 26296701, 29084914, 9429140, 21324516, 24830819, 20104584, 21120943, 27087322, 24504028, 28166811, 28087643, 27978560, 29339979, 30720243, 30322717, 31432501, 31447099, 31263571, 31948886, 32853339, 30787465, 33087929)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000195404	SCV000271332	pathogenic	Hereditary breast ovarian cancer syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The p.Leu2357ValfsX2 variant in BRCA2 has been identified in >30 individuals with BRCA2-associated cancers (Garvin 1997, Spearman 2008, Borg 2010, Caux-Moncoutier 2011, Zhang 2011, Breast Cancer Information Core (BIC) database). This variant has also been identified in 7/12892 European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2357 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in individuals with HBOC. In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282439.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PS4, PM2.
Color Diagnostics, LLC DBA Color Health	RCV000131032	SCV000292173	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 14 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 7297delCT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals affected with breast and/or ovarian cancer (PMID: 9667259, 16234499, 18824701, 20104584, 21324516, 21913181, 24504028, 24549055, 24728189), as well as colorectal cancer (PMID: 27978560) and high grade prostate cancer (PMID: 34700141). This variant has been identified in 7/282332 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000045136	SCV000296725	pathogenic	not provided	2023-05-08	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000054 (7/128928 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 9429140 (1997)), ovarian cancer (PMID: 29084914 (2018), 30322717 (2018), 31263571 (2019)), colorectal cancer (PMID: 27978560 (2016)), and pancreatic cancer (PMID: 31948886 (2020), 32853339 (2021)). Based on the available information, this variant is classified as pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031664	SCV000327588	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000031664	SCV000488257	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-04	criteria provided, single submitter	clinical testing
Genologica Medica	RCV000031664	SCV000577969	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-01-01	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000031664	SCV000605676	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195404	SCV000695036	pathogenic	Hereditary breast ovarian cancer syndrome	2017-08-07	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.7069_7070delCT (p.Leu2357Valfs) 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.7133C>G [p.Ser2378X], c.7180A>T [p.Arg2394X], and c.7360delA [p.Ile2454fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.000033 (4/121100 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been identified in numerous patients in published reports (e.g., Thomassen_Acta Oncol_2008). 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	RCV000031664	SCV000744510	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000031664	SCV000804428	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-11	criteria provided, single submitter	provider interpretation	This 6 year old male with global developmental delays (at-risk for mild intellectual disability), ADHD, disruptive behavior, and mild overgrowth was found to carry a maternally inherited 2 bp deletion in the BRCA2 gene. The c.7069_7070delCT pathogenic variant in the BRCA2 gene, previously reported as 7297delCT using alternate nomenclature, has been published in association with early-onset breast cancer, ovarian cancer, and prostate cancer (Garvin et al., 1997; Zhang et al., 2011; Cunningham et al., 2014; Song et al., 2014; Ellingson et al., 2015; Decker et al., 2016). The deletion causes a frameshift and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Given that this is an adult-onset condition, the patient is not expected to be affected at this time. The patient's mother has not been formally evaluated in the oncology setting, so her current status is unknown.
Mendelics	RCV000195404	SCV000838849	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000045136	SCV001160239	pathogenic	not provided	2023-06-19	criteria provided, single submitter	clinical testing	The BRCA2 c.7069_7070del; p.Leu2357ValfsTer2 variant (rs80359636), also known as 7297delCT, has been reported in multiple individuals with early onset breast or ovarian cancer (Caux-Moncoutier 2011, Cunningham 2014, Garvin 1997, Zhang 2011). It is listed as pathogenic in ClinVar (Variation ID: 38082) and is observed 7 times in the Genome Aggregation Database (7/276,822 alleles). This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the variant is considered to be pathogenic. References: Caux-Moncoutier V et al. EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. Hum Mutat. 2011; 32(3):325-34. PMID: 21120943. Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. PMID: 24504028. Garvin A et al. BRCA1 and BRCA2 mutation analysis in 86 early onset breast/ovarian cancer patients. J Med Genet. 1997; 34(12):990-5. PMID: 9429140. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011; 121(2):353-7. PMID: 21324516.
CeGaT Center for Human Genetics Tuebingen	RCV000045136	SCV001249490	pathogenic	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000031664	SCV001434856	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-08-06	criteria provided, single submitter	clinical testing	This c.7069_7070delCT (p.Leu2357Valfs*2) frameshift variant in the BRCA2 gene is predicted to introduce a premature translation termination codon. It has been reported in multiple unrelated patients and families affected with breast cancer [PMID 9429140, 18465347, 21120943, 21324516, 24504028] and is extremely rare in general population. Therefore, this variant in the BRCA2 gene is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000045136	SCV001448153	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310136	SCV001499684	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000045136	SCV002761181	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000031664	SCV002761530	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-08-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000045136	SCV003816123	pathogenic	not provided	2023-11-29	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149600	SCV003838832	pathogenic	Breast and/or ovarian cancer	2021-10-20	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031664	SCV004100706	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-05	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4,PM5_STR
Baylor Genetics	RCV003473208	SCV004211885	pathogenic	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000045136	SCV004226621	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	PP5, PM2, PVS1
Institute of Human Genetics, University of Leipzig Medical Center	RCV003473208	SCV004812135	pathogenic	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM5_STR
All of Us Research Program, National Institutes of Health	RCV000031664	SCV004844359	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-02-05	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 14 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 7297delCT in the literature according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals affected with breast and/or ovarian cancer (PMID: 9667259, 16234499, 18824701, 20104584, 21324516, 21913181, 24504028, 24549055, 24728189), as well as colorectal cancer (PMID: 27978560) and high grade prostate cancer (PMID: 34700141). This variant has been identified in 7/282332 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.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000031664	SCV005045980	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Baylor Genetics	RCV000031664	SCV005049484	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-03-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786284	SCV005398548	pathogenic	Fanconi anemia complementation group D1	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant BRCA2-related cancer and recessive fanconi anemia, complementation group D1 (MIM#605724). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. BRCA2-related cancers are known to have incomplete penetrance (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a condition (7 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and has been observed in individuals with breast, ovarian and colorectal cancers (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Sharing Clinical Reports Project (SCRP)	RCV000031664	SCV000054271	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-04-23	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031664	SCV000147015	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	RCV000195404	SCV000587883	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353880	SCV000592097	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Leu2357ValfsX2 variant was identified in 2 of 2856 proband chromosomes (frequency: 0.001) from individuals or families with Breast and/or Ovarian cancer (Garvin, 1997; Zhang, 2011). The variant was also identified in dbSNP (ID: rs80359636) “With pathogenic allele”, HGMD, LOVD, ClinVar database, the BIC database (31X with Important clinical importance), and UMD (34X as a class 5-causal variant). The variant was classified as a pathogenic variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Leu2357ValfsX2 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2357 and leads to a premature stop codon 2 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031664	SCV000733293	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000045136	SCV001905759	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031664	SCV004243752	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541046	SCV004762720	pathogenic	BRCA2-related disorder	2023-12-12	no assertion criteria provided	clinical testing	The BRCA2 c.7069_7070delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu2357Valfs*2). This variant has been reported to be causative for hereditary cancer such as breast, ovarian, or colorectal cancers (reported as 7297delCT in Garvin et al. 1997. PubMed ID: 9429140; eTable 3, Pearlman et al. 2017. PubMed ID: 27978560; Table S3, Labidi-Galy et al. 2018. PubMed ID: 29084914; Heramb et al. 2018. PubMed ID: 29339979). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38082/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.