Submissions for variant NM_000059.4(BRCA2):c.5722_5723del (p.Leu1908fs)

dbSNP: rs80359530

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)	RCV000009905	SCV000282413	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	RCV000044728	SCV000072741	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1908Argfs*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 (rs80359530, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 8524414, 20736950, 20927582, 21324516, 22535016, 23028338, 24963353, 25940717, 27553291). It has also been observed to segregate with disease in related individuals. This variant is also known as 5950delCT. ClinVar contains an entry for this variant (Variation ID: 9320). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131120	SCV000186050	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-21	criteria provided, single submitter	clinical testing	The c.5722_5723delCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 5722 to 5723, causing a translational frameshift with a predicted alternate stop codon (p.L1908Rfs*2). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome cohorts, including individuals with male breast cancer, pancreatic cancer and prostate cancer (Wooster R et al. Nature. 1995 Dec;378:789-92; Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Cherbal F et al. Dis Markers, 2010;28:377-84; Ding YC et al. Breast Cancer Res. Treat. 2011 Apr;126:771-8; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7; Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Johns AL et al. Genome Med. 2014 May;6:42; Ruiz A et al. Biomed Res Int. 2014 Jun;2014:542541; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Holter S et al. J. Clin. Oncol. 2015 Oct;33:3124-9; de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Rashid MU et al. BMC Cancer. 2016 08;16:673; Na R et al. Eur Urol, 2017 05;71:740-747; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Momozowa Y et al. Nat Commun. 2018 10;9(1):4083; Wang H et al. Medicine (Baltimore), 2019 Oct;98:e17443; Guo Y et al. Biosci Rep, 2019 04;39; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; De Talhouet S et al. Sci Rep, 2020 04;10:7073; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Abdel-Razeq H et al. Sci Rep, 2021 07;11:14906). Of note, this mutation is also designated as 5950delCT and c.5718_5719del 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	RCV000009905	SCV000195991	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000160297	SCV000210768	pathogenic	not provided	2019-12-01	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 individuals with a personal or family history consistent with pathogenic variants in this gene (Wooster 1995, Frank 1998, Couch 2007, Cherbal 2010, de Juan 2015, Holter 2015, Johns 2017, Pritzlaff 2017); 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 c.5950delCT; This variant is associated with the following publications: (PMID: 21324516, 20736950, 25136594, 17301269, 19353265, 28008555, 27553291, 29339979, 29335924, 29752822, 22535016, 20683152, 12181777, 26026974, 24830819, 23028338, 9667259, 17453335, 20104584, 22798144, 16835750, 12112655, 12048272, 14973102, 25863477, 8524414, 25940717, 27836010, 26843898, 25330149, 28454591, 27989354, 29470806, 28724667, 30720863, 30940775, 30078507, 30287823, 30720243, 30702160, 31528241, 31577767, 31447099, 31980526)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735574	SCV000219360	pathogenic	Breast and/or ovarian cancer	2023-06-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000160297	SCV000225178	pathogenic	not provided	2015-05-04	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000044728	SCV000271330	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-23	criteria provided, single submitter	clinical testing	The p.Leu1908ArgfsX2 variant in BRCA2 has been reported in >60 individuals with BRCA2-associated cancers (Kwong 2009 PMID: 19353265, Cherbal 2010 PMID: 20683152, Zhang 2011, Edwards 2010 PMID: 20736950, Rebbeck 2018 PMID: 29446198, Breast Cancer Information Core (BIC) database). It has also been identified in 0.003% (1/30598) of South Asian chromosomes by 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 1908 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 HBOC. Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 9320). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP criteria applied: PVS1, PS4, PM2_Supporting.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160297	SCV000296745	pathogenic	not provided	2023-06-12	criteria provided, single submitter	clinical testing	The BRCA2 c.5722_5723del (p.Leu1908Argfs*2) 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 individuals with breast and/or ovarian cancer (PMID: 30940775 (2019), 32341426 (2020), 34290354 (2021)), including male individuals with breast cancer (PMID: 20927582 (2011), 23028338 (2012)). This variant has also been reported in individuals with prostate cancer (PMID: 20736950 (2010)), and pancreatic cancer (PMID: 25940717 (2015), 31577767 (2019)). The frequency of this variant in the general population, 0.000004 (1/250888 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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	RCV000009905	SCV000327270	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000461157	SCV000541000	pathogenic	Familial cancer of breast	2024-03-21	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000009905	SCV000605675	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-07-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000009905	SCV000677689	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-05-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131120	SCV000683728	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-04	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 5950delCT, 5946delCT and 5950-5951delCT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 12 individuals affected with breast and/or ovarian cancer (PMID: 8665505, 14647210, 19353265, 20683152, 21324516, 24010542, 25136594, 26026974, 27553291, 28724667, 29470806, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001607) and five individuals affected with pancreatic cancer (PMID: 24963353, 25940717) or prostate cancer (PMID: 20736950, 31214711). This variant also has been reported in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 8524414, 11802209, 15340362, 16234499, 25863477). This variant has been identified in 1/250888 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.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000009905	SCV001434852	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2018-10-12	criteria provided, single submitter	clinical testing	This c.5722_5723del (p.Leu1908Argfs*2) variant in the BRCA2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated individuals with breast cancer or ovarian cancer (PMID 8524414, 20927582, 21324516, 24010542, 25863477, 27553291), pancreatic cancer (PMID 25940717) and prostate cancer (PMID 20736950). This variant is extremely rare in general population database. Therefore, this c.5722_5723del (p.Leu1908Argfs*2) variant in the BRCA2 gene is classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000160297	SCV001447288	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000160297	SCV001450048	pathogenic	not provided	2019-04-18	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310125	SCV001499673	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000160297	SCV001501473	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	BRCA2: PVS1, PM2, PS4:Moderate
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044728	SCV001572444	pathogenic	Hereditary breast ovarian cancer syndrome	2021-04-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5722_5723delCT (p.Leu1908ArgfsX2) 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. The variant allele was found at a frequency of 4e-06 in 250888 control chromosomes. c.5722_5723delCT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). 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. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000160297	SCV002016831	pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing
University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	RCV000009905	SCV002104287	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131120	SCV002536167	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-16	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496315	SCV002809681	pathogenic	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2021-11-02	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160297	SCV003800108	pathogenic	not provided	2022-04-28	criteria provided, single submitter	clinical testing	The BRCA2 c.5722_5723delCT; p.Leu1908ArgfsTer2 variant (rs80359530), also known as 5950delCT, has been described in several individuals and families affected with breast, ovarian, prostate, or pancreatic cancers (Cherbal 2010, de Juan 2015, Ding 2011, Edwards 2010, Holter 2015, Kwong 2009, Thompson 2012, Zhang 2011). This variant is reported in ClinVar (Variation ID: 9320) and is classified as pathogenic by an expert panel. This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 2 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 pathogenic. REFERENCES Cherbal F et al. BRCA1 and BRCA2 germline mutations screening in Algerian breast/ovarian cancer families. Dis Markers. 2010;28(6):377-84. PMID: 20683152. de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015 Dec;14(4):505-13. PMID: 26026974. Ding Y et al. Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States. Breast Cancer Res Treat. 2011 Apr;126(3):771-8. PMID: 20927582. Edwards S et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010 Sep 7;103(6):918-24. PMID: 20736950. Holter S et al. Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma. J Clin Oncol. 2015 Oct 1;33(28):3124-9. PMID: 25940717. Kwong A et al. A BRCA2 founder mutation and seven novel deleterious BRCA mutations in southern Chinese women with breast and ovarian cancer. Breast Cancer Res Treat. 2009 Oct;117(3):683-6. PMID: 19353265. Thompson E et al. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet. 2012 Sep;8(9):e1002894. PMID: 23028338. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. PMID: 21324516.
Eurofins-Biomnis	RCV000461157	SCV003935057	pathogenic	Familial cancer of breast	2022-10-25	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000009905	SCV004846633	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-15	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 5950delCT, 5946delCT and 5950-5951delCT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 12 individuals affected with breast and/or ovarian cancer (PMID: 8665505, 14647210, 19353265, 20683152, 21324516, 24010542, 25136594, 26026974, 27553291, 28724667, 29470806, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001607) and five individuals affected with pancreatic cancer (PMID: 24963353, 25940717) or prostate cancer (PMID: 20736950, 31214711). This variant also has been reported in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 8524414, 11802209, 15340362, 16234499, 25863477). This variant has been identified in 1/250888 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	RCV000009905	SCV005045903	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Department of Human Genetics, Hannover Medical School	RCV000009905	SCV005068269	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-07-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160297	SCV005090043	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000160297	SCV005199519	pathogenic	not provided	2023-02-28	criteria provided, single submitter	clinical testing
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	RCV000009905	SCV005201031	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-08-14	criteria provided, single submitter	clinical testing	Null variant (frame-shift) in gene BRCA2, predicted to cause NMD. Loss-of-function is a known mechanism of disease. The exon affects 1 functional domain: UniProt protein BRCA2_HUMAN region of interest 'Interaction with RAD51'.The truncated region contains 2 405 pathogenic variants (PVS1). Combined evidence strength is Very Strong (score = 12).Very Strong: ClinVar classifies this variant as Pathogenic, 3 starsStrong: LOVD classifies this variant as Pathogenic (PP5). Variant not found in gnomAD genomes, GnomAD exomes homozygous allele count = 0 is less than 2 for AD/AR gene BRCA2, (PM2).We identified this variant in a 48-year-old patient diagnosed with triple-negative breast cancer.
OMIM	RCV000009905	SCV000030126	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1995-12-21	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000009905	SCV000054177	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2013-03-28	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000009905	SCV000146677	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	RCV000044728	SCV000587796	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000160297	SCV000591992	pathogenic	not provided		no assertion criteria provided	clinical testing	The p.Leu1908ArgfsX2 deletion variant has been previously reported in the literature in at least 4 of 3460 proband chromosomes in individuals with hereditary breast, ovarian or pancreatic cancer and was shown to segregate with disease in one family (Selected publications: Edwards 2010, Heidemann 2012, Kwong 2009, Zhang 2011). In addition, it was reported 17x in the UMD database as causal and 42X in the BIC database as having clinical importance. This DNA alteration leads to a premature stop codon at position 1908, which is predicted to lead to 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. In summary, this variant is classified as pathogenic.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735574	SCV000863712	pathogenic	Breast and/or ovarian cancer	2015-05-15	no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV000461157	SCV002520809	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000009905	SCV002588891	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162224	SCV002758433	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research