Total submissions: 33
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Evidence- |
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 | 2019-12-30 | 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. |
Gene |
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, |
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, |
RCV000210073 | SCV000266043 | pathogenic | Breast-ovarian cancer, familial 1 | 2015-11-20 | criteria provided, single submitter | clinical testing | |
Color Health, |
RCV000131858 | SCV000292146 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-01-15 | criteria provided, single submitter | clinical testing | |
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 |
RCV000031637 | SCV000327465 | pathogenic | Breast-ovarian cancer, familial 2 | 2015-10-02 | criteria provided, single submitter | clinical testing | |
Integrated Genetics/Laboratory Corporation of America | 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 | |
Hudson |
RCV000031637 | SCV000584073 | pathogenic | Breast-ovarian cancer, familial 2 | 2014-07-10 | criteria provided, single submitter | research | |
Department of Medical Genetics, |
RCV000031637 | SCV000605688 | pathogenic | Breast-ovarian cancer, familial 2 | 2015-10-06 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular 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. |
DNA and Cytogenetics Diagnostics Unit, |
RCV000031637 | SCV000744390 | pathogenic | Breast-ovarian cancer, familial 2 | 2015-09-21 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV000074548 | SCV000805748 | pathogenic | not provided | 2014-09-03 | criteria provided, single submitter | clinical testing | |
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. |
Ce |
RCV000074548 | SCV001247635 | pathogenic | not provided | 2019-04-01 | criteria provided, single submitter | clinical testing | |
Institute of Medical Genetics and Applied Genomics, |
RCV000074548 | SCV001447718 | pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Clinical Genetics Karolinska University Hospital, |
RCV000074548 | SCV001449833 | pathogenic | not provided | 2015-11-18 | criteria provided, single submitter | clinical testing | |
Department of Molecular Diagnostics, |
RCV000210073 | SCV001499761 | pathogenic | Breast-ovarian cancer, familial 1 | 2020-04-02 | 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 |
RCV000031637 | SCV000054244 | pathogenic | Breast-ovarian cancer, familial 2 | 2014-01-04 | no assertion criteria provided | clinical testing | |
Breast Cancer Information Core |
RCV000031637 | SCV000147427 | pathogenic | Breast-ovarian cancer, familial 2 | 2002-05-29 | no assertion criteria provided | clinical testing | |
Research Molecular Genetics Laboratory, |
RCV000044988 | SCV000587560 | pathogenic | Hereditary breast and ovarian cancer syndrome | 2014-01-31 | no assertion criteria provided | research | |
Diagnostic Laboratory, |
RCV000031637 | SCV000733216 | pathogenic | Breast-ovarian cancer, familial 2 | no assertion criteria provided | clinical testing | ||
Mayo Clinic Genetic Testing Laboratories, |
RCV000074548 | SCV000778635 | pathogenic | not provided | 2016-12-27 | no assertion criteria provided | clinical testing | |
Foulkes Cancer Genetics LDI, |
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 |