Submissions for variant NM_000059.4(BRCA2):c.2092del (p.Leu698fs)

gnomAD frequency: 0.00001  dbSNP: rs80359322

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031355	SCV000300491	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	RCV000221559	SCV000071955	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.Leu698Tyrfs*32) 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 cancer (PMID: 15887246, 26681312). This variant is also known as 2320delC. ClinVar contains an entry for this variant (Variation ID: 37774). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000212218	SCV000210720	pathogenic	not provided	2025-03-28	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 personal or family history consistent with pathogenic variants in this gene (PMID: 15887246, 16550498); 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 2320del; 2320delC; This variant is associated with the following publications: (PMID: 16550498, 32073954, 15887246, 26681312, 32341426, 30787465, 26740259, 32427313, 31853058, 29446198, 22762150, 20104584)
Ambry Genetics	RCV000166692	SCV000217500	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	clinical testing	The c.2092delC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 2092, causing a translational frameshift with a predicted alternate stop codon (p.L698Yfs*32). This mutation has been reported in multiple individuals with herediatry breast and/or ovarian cancer (Bonadona V et al. Genes Chromosomes Cancer 2005 Aug; 43(4):404-13; Susswein LR et al. Genet. Med. 2016 08;18(8):823-32; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). Of note, this mutation is also designated as 2320delC 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221559	SCV000271323	pathogenic	Hereditary breast ovarian cancer syndrome	2022-11-03	criteria provided, single submitter	clinical testing	The p.Leu698fs variant in BRCA2 has been reported in 2 individuals with breast cancer (Bonadona 2005 PMID: 15887246, Susswein 2015 PMID: 26681312). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 698 and leads to a premature termination codon 32 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 for hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) for HBOC in an autosomal dominant. ACMG/AMP criteria applied: PVS1, PM2_Supporting, PS4_Supporting.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031355	SCV000326652	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212218	SCV000805664	pathogenic	not provided	2017-09-08	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000031355	SCV001132515	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-04-12	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000221559	SCV002074172	pathogenic	Hereditary breast ovarian cancer syndrome	2022-01-10	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2092delC (p.Leu698TyrfsX32) 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 250696 control chromosomes. c.2092delC has been reported in the literature in individuals affected with Breast, Ovarian, and Prostate Cancer (example: Palmer_2020, De Talhouet_2020, Bonadona_2005, Susswein_2016, Wu_2018, Weber_2006) and was screened for patients with elevated risk for Breast and Ovarian cancer (example: Rebbeck_2018, Lecarpentier_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters, including one expert panel and one consortia, have assessed the variant since 2014: all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV000166692	SCV002533291	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-14	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000031355	SCV003932345	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu698Tyrfs*32) 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 (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 15887246, 26681312). This variant is also known as 2320delC. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003473161	SCV004211814	pathogenic	Familial cancer of breast	2024-02-27	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031355	SCV000053960	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2011-05-27	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031355	SCV000146002	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing