ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.631+2T>G (rs81002899)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031615 SCV001161558 pathogenic Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.998311
Invitae RCV000195357 SCV000072910 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous or compound heterozygous with other pathogenic BRCA2 variants in individuals affected with Fanconi anemia (PMID: 21719596, 15070707, 16825431, 15645491). It has also been observed in individuals affected with breast and/or ovarian cancer (PMID: 11185744, 25682074, 26296701). This variant is also known as IVS7+2T>G in the literature. ClinVar contains an entry for this variant (Variation ID: 9349). This variant falls in intron 7 of the BRCA2 mRNA and is reported to cause skipping of exon 7 (PMID: 11185744, 21719596). The absence of exon 7 in the BRCA2 mRNA results in a translational frameshift and premature stop codon (p.Gly173Serfs*18) that may produce an unstable protein (PMID: 21719596). Functional analysis in mouse stem cells shows that this variant causes a severe phenotype that is unable to rescue cell lethality compared to wild-type BRCA2 (PMID: 21719596). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000129071 SCV000183773 pathogenic Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
GeneDx RCV000044897 SCV000210249 pathogenic not provided 2018-10-29 criteria provided, single submitter clinical testing This variant, denoted BRCA2 c.631+2 T>G or IVS7+2 T>G, is a splice site mutation which destroys a canonical splice donor site in intron 7. It is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been previously reported as a pathogenic variant in individuals with hereditary breast and/or ovarian cancer with functional data demonstrating that normal mRNA is not produced from the mutated allele (Pyne 2000). and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers.
Michigan Medical Genetics Laboratories,University of Michigan RCV000031615 SCV000267734 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044897 SCV000296701 pathogenic not provided 2019-06-07 criteria provided, single submitter clinical testing The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031615 SCV000327385 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031615 SCV000488785 pathogenic Breast-ovarian cancer, familial 2 2016-06-14 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000195357 SCV000591703 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-17 criteria provided, single submitter clinical testing
Color RCV000129071 SCV000683770 pathogenic Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000195357 SCV000694958 pathogenic Hereditary breast and ovarian cancer syndrome 2016-07-05 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.631+2T>G variant involves the alteration of a conserved intronic nucleotide located at the invariable splice acceptor site in intron 7 of BRCA2. One in silico tool predicts a damaging outcome for this variant along with 5/5 splice site tools predicting the variant to result in the elimination of the splice donor site in intron 7. These predictions were confirmed by Pyne_J Hum Genet_2000 demonstrating that an RNA splicing product that deletes exon 7 was produced by the chromosome that carries the variant of interest. The deletion of exon 7 from the RNA alters the open reading frame by removing residues 249287 and incorporating 18 abnormal amino acids before terminating with an opal stop codon. This variant is absent in 121164 control chromosomes while it was reported in several HBOC spectrum patients. Furthermore, multiple clinical diagnostic laboratories and reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as Pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000031615 SCV000778601 pathogenic Breast-ovarian cancer, familial 2 2019-01-22 criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769680 SCV000901093 pathogenic Breast and/or ovarian cancer 2017-09-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000826135 SCV000967655 pathogenic Fanconi anemia 2018-02-20 criteria provided, single submitter clinical testing The c.631+2T>G variant in BRCA2 has been identified in the homozygous or compoun d heterozygous state in 5 individuals with Fanconi anemia (Myer 2005, Myers 2012 , Wagner 2004), and segregated with disease in 2 individuals from 2 families. It was absent from large population studies. The c.631+2T>G variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been shown t o cause altered splicing leading to an absent protein (Pyne 2000, Meyer 2005, Bi swas 2011). In summary, this variant meets criteria to be classified as pathogen ic for Fanconi anemia in an autosomal recessive manner. ACMG/AMP criteria applie d: PVS1, PM3_VeryStrong, PS4_Moderate, PM2, PP1.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000195357 SCV000967740 pathogenic Hereditary breast and ovarian cancer syndrome 2018-02-20 criteria provided, single submitter clinical testing The c.631+2T>G variant in BRCA2 has been reported in >15 individuals with BRCA2- associated cancers (Pyne 2000, Wong-Brown 2015, Breast Cancer Information Core ( BIC) database). It was absent from large population studies. The c.631+2T>G vari ant occurs in the invariant region (+/- 1,2) of the splice consensus sequence an d has been shown to cause altered splicing leading to an absent protein (Pyne 20 00, Meyer 2005, Biswas 2011). Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC) . In summary, this variant meets criteria to be classified as pathogenic for her editary breast and ovarian cancer syndrome in an autosomal dominant manner. ACMG /AMP criteria applied: PS4, PM2, PVS1.
OMIM RCV000009943 SCV000030164 pathogenic Fanconi anemia, complementation group D1 2007-01-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000031615 SCV000054222 pathogenic Breast-ovarian cancer, familial 2 2013-01-08 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031615 SCV000147336 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 RCV000195357 SCV000587557 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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