Submissions for variant NM_000059.4(BRCA2):c.5763dup (p.Ala1922fs)

dbSNP: rs80359534

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113479	SCV000300927	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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000113479	SCV000327277	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580772	SCV000683732	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-31	criteria provided, single submitter	clinical testing	This variant inserts 1 nucleotide 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 has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 16168118, 18489799, 20353281). This variant has not been identified 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	RCV000781089	SCV000918906	pathogenic	Hereditary breast ovarian cancer syndrome	2018-04-30	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5763dupT (p.Ala1922CysfsX2) 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 (eg. c.5796_5797delTA, p.His1932fsX12; c.5799_5802delCCAA, p.Asn1933fsX29; c.5828delC, p.Ser1943fsX20). The variant was absent in 121048 control chromosomes. c.5763dupT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Machackova_2008, Mateju_2010, Pohlreich_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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.
Ambry Genetics	RCV000580772	SCV001186526	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-19	criteria provided, single submitter	clinical testing	The c.5763dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 5763, causing a translational frameshift with a predicted alternate stop codon (p.A1922Cfs*2). This alteration has been reported in individuals with breast and/or ovarian cancer (Pohlreich P et al. Breast Cancer Res. 2005 Jul;7:R728-36; Machackova E et al. BMC Cancer 2008 May;8:140; Mateju M et al. Neoplasma 2010;57:280-5; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 5991insT 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000781089	SCV001588192	pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala1922Cysfs*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 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: 15158118, 18489799). ClinVar contains an entry for this variant (Variation ID: 51931). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002477149	SCV002774327	pathogenic	not provided	2021-08-26	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 16168118 (2005), 20353281 (2010)). Based on the available information, this variant is classified as pathogenic.
Baylor Genetics	RCV003473365	SCV004210416	pathogenic	Familial cancer of breast	2023-01-17	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113479	SCV000146691	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV001271041	SCV001451860	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing