Submissions for variant NM_000059.4(BRCA2):c.262_263del (p.Leu88fs)

dbSNP: rs276174825

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113331	SCV000282370	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	RCV000044028	SCV000072041	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu88Alafs*12) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15146557, 20151322, 23683081, 24578176, 25940717). This variant is also known as 488delCT and 490delCT. ClinVar contains an entry for this variant (Variation ID: 51317). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000162895	SCV000213382	pathogenic	Hereditary cancer-predisposing syndrome	2025-01-02	criteria provided, single submitter	clinical testing	The c.262_263delCT pathogenic mutation, located in coding exon 2 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 262 to 263, causing a translational frameshift with a predicted alternate stop codon (p.L88Afs*12). This mutation has been identified in multiple breast, ovarian, and/or pancreatic cancer families in the literature from diverse populations (Gorski B et al. Int J Cancer. 2004 Jul 10;110(5):683-6; Thirthagiri E et al. Breast Cancer Res. 2008;10(4):R59; Novakovic S et al. Int J Oncol. 2012 Nov;41(5):1619-27; Blay P et al. BMC Cancer. 2013 May 17;13:243; Holter S et al. J. Clin. Oncol. 2015 Oct;33(28):3124-9; de Juan I et al. Fam. Cancer 2015 Dec;14(4):505-13; Wen WX et al. J. Med. Genet.,2018 02;55:97-103; Chan GHJ et al. Oncotarget. 2018 Jul;9:30649-30660; Bhaskaran SP et al. Int. J. Cancer. 2019 08;145:962-973). Of note, this alteration is also designated as 490delCT and 488delCT in some 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113331	SCV000326735	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000523679	SCV000617459	pathogenic	not provided	2024-09-15	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 490_491del; This variant is associated with the following publications: (PMID: 28127413, 15146557, 25072261, 22923021, 33754277, 26843898, 23683081, 24578176, 20151322, 18627636, 26187060, 25940717, 26026974, 21614564, 29940740, 28724667, 28993434, 30702160, 30093976, 31825140, 30875412, 30787465, 31853058, 36385461, 36367610, 36135357, 35864222, 38003901, 38922859)
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000113331	SCV000744380	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000523679	SCV000889007	pathogenic	not provided	2023-01-31	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. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28724667 (2017), 26026974 (2015), 20151322 (2010), 18627636 (2008), and 15146557 (2004)), as well as pancreatic cancer (PMID: 25940717 (2015) and 25072261 (2014)). Based on the available information, this variant is classified as pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310164	SCV001499758	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492349	SCV004240300	likely pathogenic	Breast and/or ovarian cancer	2023-04-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113331	SCV000146469	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2010-07-16	no assertion criteria provided	clinical testing
Counsyl	RCV000113331	SCV000489212	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2016-09-07	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000113331	SCV000733209	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000113331	SCV005061308	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-24	no assertion criteria provided	case-control