Submissions for variant NM_000059.4(BRCA2):c.5164_5165del (p.Ser1722fs)

gnomAD frequency: 0.00001  dbSNP: rs80359490

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077346	SCV000300838	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044579	SCV000072592	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1722Tyrfs*4) 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 (rs80359490, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150154, 19353265, 22160602, 24321281, 26848529, 27157322). This variant is also known as 5392delAG and 5392-5393delAG. ClinVar contains an entry for this variant (Variation ID: 51791). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000077346	SCV000220974	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2014-12-22	criteria provided, single submitter	literature only
Ambry Genetics	RCV000216136	SCV000273839	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-27	criteria provided, single submitter	clinical testing	The c.5164_5165delAG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 5164 to 5165, causing a translational frameshift with a predicted alternate stop codon (p.S1722Yfs*4). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) families, which include individuals with male breast cancer and pancreatic cancer (Håkansson S et al. Am. J. Hum. Genet. 1997 May;60:1068-78; Ganguly A et al. Am. J. Med. Genet. 2001 Jun;101:146-52; Kwong A et al. Breast Cancer Res. Treat. 2009 Oct;117:683-6; Schneegans SM et al. Fam. Cancer. 2012 Jun;11:181-8; Li D et al. J Exp Clin Cancer Res, 2013 Dec;32:102; Kim YC et al. Oncotarget 2016 Feb;7(8):9600-12; Ng PS et al. Clin. Genet. 2016 Oct:90:315-23; Chao A et al. Oncotarget 2016 Dec;7(51):85529-85541; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Liang Y et al. Med Sci Monit, 2018 Apr;24:2465-2475;Bannon SA et al. Cancer Prev Res (Phila), 2018 11;11:679-686; Wang YA et al. BMC Cancer, 2018 03;18:315; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Li JY et al. Int. J. Cancer. 2019 Jan;144(2):281-289; Wu H et al. Hum Hered, 2019 Feb;84:160-169; Deng H et al. Mol Genet Genomic Med, 2019 06;7:e672; Chen L et al. Breast Cancer Res Treat, 2020 Apr;180:759-766; Meng H et al. Int J Cancer, 2020 06;146:3044-3052; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000482731	SCV000296557	pathogenic	not provided	2023-01-20	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, 0.000032 (1/31360 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 32072338 (2020), 31957001 (2020), 30702160 (2019), 32101877 (2019), 30972954 (2019), 29752822 (2018), 19353265 (2009), 9150154 (1997)). 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	RCV000077346	SCV000327153	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000482731	SCV000568471	pathogenic	not provided	2024-09-30	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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5392_5393del; This variant is associated with the following publications: (PMID: 22160602, 27157322, 26848529, 28008555, 11391658, 36853301, 35864222, 35918668, 28324225, 27907908, 38167124, 28888541, 34697415, 9150154, 19353265, 24321281, 26757417, 26833046, 15744030, 26824983, 29566657, 28724667, 29752822, 29907814, 26295337, 30274973, 30078507, 30720243, 30702160, 30972954, 31957001, 32072338, 32467295, 31825140, 30787465, 32101877, 33461583)
Color Diagnostics, LLC DBA Color Health	RCV000216136	SCV000683680	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-19	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 expected to result in an absent or non-functional protein product. This variant is also known as 5392delAG in the literature. This variant has been reported in at least 10 individuals affected with breast and/or ovarian cancer (PMID: 9150154, 11391658, 19353265, 27907908, 29752822, 30972954, 32101877, 31957001, 33471991). This variant has been identified in 1/31360 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044579	SCV001337848	pathogenic	Hereditary breast ovarian cancer syndrome	2020-01-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5164_5165delAG (p.Ser1722TyrfsX4) 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 was absent in 233676 control chromosomes. c.5164_5165delAG has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (eg. Bhaskaran_2019, Chao_2016, Hakansson_1997, Schneegans_2012). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000482731	SCV001448110	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002250515	SCV002579485	pathogenic	Familial cancer of breast	2021-12-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077346	SCV004845778	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-08	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 expected to result in an absent or non-functional protein product. This variant is also known as 5392delAG in the literature. This variant has been reported in at least 10 individuals affected with breast and/or ovarian cancer (PMID: 9150154, 11391658, 19353265, 27907908, 29752822, 30972954, 32101877, 31957001, 33471991). This variant has been identified in 1/31360 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	RCV000077346	SCV005045994	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-05-27	criteria provided, single submitter	clinical testing	PVS1; PM5_PTC_Strong
Baylor Genetics	RCV002250515	SCV005059064	pathogenic	Familial cancer of breast	2024-02-11	criteria provided, single submitter	clinical testing
Department of Human Genetics, Hannover Medical School	RCV000077346	SCV005201117	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-09-10	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077346	SCV000109143	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-09-27	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077346	SCV000146553	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	1997-11-13	no assertion criteria provided	clinical testing
Center for Precision Medicine, Meizhou People's Hospital	RCV002250515	SCV002520798	pathogenic	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV000077346	SCV004243656	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing