Submissions for variant NM_000059.4(BRCA2):c.658_659del (rs80359604)

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031637	SCV000282430	pathogenic	Breast-ovarian cancer, familial 2	2016-04-22	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Invitae	RCV000044988	SCV000073001	pathogenic	Hereditary breast and ovarian cancer syndrome	2020-11-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val220Ilefs*4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs768580992, ExAC 0.01%). This variant has been observed in individual(s) affected with hereditary breast and ovarian cancer (PMID: 9667259, 22923021, 23767878, 24504028), and Fanconi anemia (PMID: 26657402). This variant is also known as 886delGT in the literature. ClinVar contains an entry for this variant (Variation ID: 9342). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000074548	SCV000108633	pathogenic	not provided	2017-01-24	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted BRCA2 c.658_659delGT at the cDNA level and p.Val220IlefsX4 (V220IfsX4) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AACT[delGT]ATTT. The deletion causes a frameshift, which changes a Valine to an Isoleucine at codon 220, and creates a premature stop codon at position 4 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.658_659delGT, previously reported as 886delGT using alternate nomenclature, has been reported in multiple individuals from hereditary breast and ovarian cancer families (Frank 1998, Jakubowska 2003, Machado 2007, Berzina 2013, Cunningham 2014, de Juan 2015) and has been observed in the compound heterozygous state with a second pathogenic BRCA2 variant in patients with Fanconi anemia (Alter 2007, Miele 2015). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics	RCV000131858	SCV000186913	pathogenic	Hereditary cancer-predisposing syndrome	2018-11-09	criteria provided, single submitter	clinical testing	The c.658_659delGT pathogenic mutation, located in coding exon 7 of the BRCA2 gene, results from a deletion of 2 nucleotides at positions 658 to 659, causing a translational frameshift with a predicted alternate stop codon (p.V220Ifs*4). This mutation has been described in numerous HBOC families (Frank TS et al. J. Clin. Oncol. 1998 Jul;16:2417-25; Berzina D et al. BMC Med. Genet. 2013;14:61; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). This mutation has also been observed in Fanconi anemia group D1 patients and was associated with brain tumors (medulloblastomas and glioblastomas) and Wilms tumor in these patients (Alter BP et al. J. Med. Genet. 2007 Jan;44:1-9; Miele E et al. Biomark Res. 2015;3:13). Of note, this alteration is also designated as 886delGT 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 classified as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Michigan Medical Genetics Laboratories,University of Michigan	RCV000031637	SCV000195951	pathogenic	Breast-ovarian cancer, familial 2	2014-11-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000031637	SCV000221117	pathogenic	Breast-ovarian cancer, familial 2	2015-02-04	criteria provided, single submitter	literature only
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210073	SCV000266043	pathogenic	Breast-ovarian cancer, familial 1	2015-11-20	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000131858	SCV000292146	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-15	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 8 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 multiple individuals affected with breast and ovarian cancer (PMID: 9667259, 22923021, 23767878, 24504028, 27153395, 28324225, 28724667, 30287823). It has also been observed in compound heterozygous state with a pathogenic variant in two individuals affected with Fanconi anemia (PMID: 16825431). This variant has been identified in 13/276414 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074548	SCV000296738	pathogenic	not provided	2019-02-22	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000031637	SCV000327465	pathogenic	Breast-ovarian cancer, familial 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044988	SCV000494408	pathogenic	Hereditary breast and ovarian cancer syndrome	2016-04-18	criteria provided, single submitter	clinical testing	Variant summary: The c.658_659delGT variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.755_758delACAG, p.Asp252fsX24; c.771_775delTCAAA, p.Asn257fsX17; c.778_779delGA, p.Glu260fsX15). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.006% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been reported in numerous affected individuals in the literature, including 2 siblings affected with Fanconi anemia who also carried a second pathogenic BRCA2 variant (Svojgr_2016). Mutliple reputable clinical labs have classified the variant as "Pathogenic". Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV000466729	SCV000540998	pathogenic	Familial cancer of breast	2017-02-23	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000031637	SCV000584073	pathogenic	Breast-ovarian cancer, familial 2	2014-07-10	criteria provided, single submitter	research
Department of Medical Genetics, Oslo University Hospital	RCV000031637	SCV000605688	pathogenic	Breast-ovarian cancer, familial 2	2015-10-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000044988	SCV000605780	pathogenic	Hereditary breast and ovarian cancer syndrome	2015-04-17	criteria provided, single submitter	clinical testing	The p.Val220fs variant in BRCA2 has been identified in >50 individuals with BRCA 2-associated cancers (Frank 1998, Berzina 2013, Breast Cancer Information Core ( BIC) database) and in 3 compound heterozygous individuals with Fanconi anemia (O ffit 2003, Hirsch 2004, Reid 2005). This variant has been identified in 4/51064 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs80359604). This variant is predicted to cause a frame shift, which alters the protein?s amino acid sequence beginning at position 220 and leads to a premature termination codon 4 amino acids downstream. This altera tion is then predicted to lead to a truncated or absent protein. In summary, thi s variant meets our criteria to be classified as pathogenic for hereditary breas t and ovarian cancer in an autosomal dominant manner based on the low frequency in controls and the predicted impact to the protein.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000031637	SCV000744390	pathogenic	Breast-ovarian cancer, familial 2	2015-09-21	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000074548	SCV000778635	pathogenic	not provided	2019-10-25	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
PreventionGenetics,PreventionGenetics	RCV000074548	SCV000805748	pathogenic	not provided	2014-09-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001000010	SCV000883510	pathogenic	not specified	2018-09-13	criteria provided, single submitter	clinical testing	The BRCA2 c.658_659delGT; p.Val220fs variant (rs80359604), also known as 886delGT, has been reported in multiple individuals with hereditary breast and ovarian cancer syndrome (Cunningham 2014, de Juan 2015, Frank 1998), and in patients with Fancomi anemia when found in-trans with another pathogenic variant (Hirsch 2004, Svojgr 2016). It is listed as pathogenic in ClinVar (Variation ID: 9342), and observed in the Genome Aggregation Database at an overall frequency of 0.004% (12/270878 alleles). This variant introduces a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based available information, this variant is considered pathogenic. REFERENCES Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015; 14(4):505-13. Frank T et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998;16(7):2417-25. Hirsch B et al. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood. 2004; 103(7):2554-9. Svojgr K et al. Fanconi anemia with biallelic FANCD1/BRCA2 mutations - Case report of a family with three affected children. Eur J Med Genet. 2016; 59(3):152-7.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000074548	SCV001247635	pathogenic	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000074548	SCV001447718	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital	RCV000074548	SCV001449833	pathogenic	not provided	2015-11-18	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000210073	SCV001499761	pathogenic	Breast-ovarian cancer, familial 1	2020-04-02	criteria provided, single submitter	clinical testing
Research and Development, ARUP Laboratories	RCV001642214	SCV001855235	pathogenic	Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome	2013-12-01	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV000031637	SCV001934294	pathogenic	Breast-ovarian cancer, familial 2	2020-11-03	criteria provided, single submitter	clinical testing
OMIM	RCV000009929	SCV000030150	pathogenic	Fanconi anemia, complementation group D1	2007-01-01	no assertion criteria provided	literature only
OMIM	RCV000009930	SCV000030151	pathogenic	Wilms tumor 1	2007-01-01	no assertion criteria provided	literature only
OMIM	RCV000009931	SCV000030152	risk factor	Glioma susceptibility 3	2007-01-01	no assertion criteria provided	literature only
OMIM	RCV000009932	SCV000030153	pathogenic	Medulloblastoma	2007-01-01	no assertion criteria provided	literature only
Sharing Clinical Reports Project (SCRP)	RCV000031637	SCV000054244	pathogenic	Breast-ovarian cancer, familial 2	2014-01-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031637	SCV000147427	pathogenic	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto	RCV000044988	SCV000587560	pathogenic	Hereditary breast and ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000031637	SCV000733216	pathogenic	Breast-ovarian cancer, familial 2		no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735587	SCV000863725	pathogenic	Breast and/or ovarian cancer	2016-12-04	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV000735587	SCV001451877	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	case-control
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001356991	SCV001552307	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val220Ilefs*4 variant was identified in 19 of 19400 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Bayraktar 2012, Berzina 2013, Frank 1998, Heidemann 2012, Janavicius 2014, Novakovic 2012). The variant was also identified in the case study in two siblings with Fanconi anemia with biallelic FANCD1/BRCA2 mutations (Svojgr 2016). The variant was also identified in dbSNP (ID: rs80359604) as “With Pathogenic allele”, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and seventeen other submitters), LOVD 3.0 (58X as pathogenic), and in UMD-LSDB (30X as causal). This mutation was found at a high frequency in the Lithuanian population and could represent a Baltic founder mutation (Janavicius 2014).The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.658_659del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 220 and leads to a premature stop codon at position 223. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in BRCA associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.