Submissions for variant NM_000059.4(BRCA2):c.2588dup (p.Asn863fs)

dbSNP: rs80359335

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031374	SCV000300532	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	RCV000044019	SCV000072032	pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn863Lysfs*18) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and Fanconi anemia (PMID: 11030417, 15070707, 21324516, 24728189). This variant is also known as 2816insA. ClinVar contains an entry for this variant (Variation ID: 37793). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768587	SCV000219316	pathogenic	Breast and/or ovarian cancer	2015-12-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000218358	SCV000274641	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-28	criteria provided, single submitter	clinical testing	The c.2588dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 2588, causing a translational frameshift with a predicted alternate stop codon (p.N863Kfs*18). This mutation has been identified in multiple individuals with personal and/or family histories of breast, ovarian, and pancreatic cancers (Gao Q et al. Hum. Genet. 2000 Aug;107:186-91; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Park JS et al. Clin Breast Cancer, 2018 10;18:362-373.e1; Dorling et al. N Engl J Med. 2021 02;384:428-439). Reports of this alteration in individuals of French Canadian ancestry suggest a founder effect in this population (Tonin PN et al. Am. J. Hum. Genet. 1998 Nov;63:1341-51; Cavallone L et al. Fam. Cancer 2010 Dec;9:507-17). This mutation was identified in a 5-year old boy with Fanconi Anemia, with a second unidentified splicing alteration suspected based on cDNA analysis (Wagner JE et al. Blood 2004 Apr;103:3226-9). Of note, this alteration is also designated as 2816insA 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031374	SCV000326727	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000296013	SCV000329135	pathogenic	not provided	2023-02-24	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 multiple individuals with a personal and/or family history of BRCA2-related cancers (Tonin et al., 1998; Kanaan et al., 2003; Cavallone et al., 2010; Song et al., 2014; Rebbeck et al., 2018) and in an individual with Fanconi anemia (Wagner et al., 2004); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2816dupA and 2816insA; This variant is associated with the following publications: (PMID: 25863477, 29922827, 28888541, 11030417, 21324516, 9792861, 15382066, 16905680, 25884701, 10422801, 24728189, 15645491, 17851763, 24301060, 15070707, 15131399, 12942367, 9667259, 20694749, 17148771, 15004464, 16847550, 25428789, 30130155, 29446198, 30702160, 31825140, 30787465, 33471991)
Fulgent Genetics, Fulgent Genetics	RCV000031374	SCV000575727	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000296013	SCV000887781	pathogenic	not provided	2023-10-10	criteria provided, single submitter	clinical testing	The BRCA2 c.2588dup (p.Asn863Lysfs*18) variant (also known as 2816insA) alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 29673794 (2018), 24728189 (2014), 21324516 (2011), 20694749 (2010), 11030417 (2000), 9792861 (1998)), and in an individual with Fanconi anemia (PMID: 15070707 (2004)). The frequency of this variant in the general population, 0.0000088 (2/227148 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000218358	SCV000903410	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-12	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 affected with breast cancer (PMID: 16760289, 25428789, 30130155) and ovarian cancer (PMID: 21324516, 24728189). This variant has been identified in 2/227148 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	RCV000044019	SCV001363893	pathogenic	Hereditary breast ovarian cancer syndrome	2019-02-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2588dupA (p.Asn863LysfsX18) 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. The variant was absent in 222684 control chromosomes (gnomAD). c.2588dupA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Gao_2000, Frank_1998, Euhus_2002, Kanaan_2003, Risch_2006, Zheng_2018). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000296013	SCV002010727	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473166	SCV004210412	pathogenic	Familial cancer of breast	2024-03-19	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031374	SCV004847070	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-10	criteria provided, single submitter	clinical testing	The c.2588dup (p.Asn863Lysfs*18) variant in the BRCA2 gene is located on the exon 11 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Asn863Lysfs*18), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 25863477, 20694749, 21324516, 12942367, 9792861). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 37793) and reviewed by the expert panel. The variant is rare in general population according to gnomAD (2/227148). Therefore, the c.2588dup (p.Asn863Lysfs*18) variant of BRCA2 has been classified as pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000031374	SCV000053979	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031374	SCV000146075	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	RCV000044019	SCV000587637	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000031374	SCV000591812	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The p.Asn862LysfsX18 duplication variant has been previously reported in the literature in 2 of 2740 chromosomes from individuals with hereditary breast and or ovarian cancer (pancreatic cancer was also suspected in one family) (Gao 2000, Zhang 2011). The variant is also reported in the UMD (3x as causal) and BIC (11x as clinically important) databases. In addition, it was reported in 3/4403 chromosomes from the exome variant server database and in dbSNP (ID#:rs80359335) in individuals of African American ancestry, increasing the likelihood this variant may be present at low frequency in this population. The p.Asn862LysfsX18 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 862 and leads to a premature stop codon 18 amino acids downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of hereditary breast and ovarian cancer for the BRCA2 gene. In summary, based on the above information, this variant is classified as pathogenic.
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)	RCV000031374	SCV005061316	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2021-05-24	no assertion criteria provided	case-control