ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8755-1G>A (rs81002812)

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Total submissions: 23
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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) RCV000031766 SCV000282251 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 = 0.999891
Invitae RCV000220836 SCV000073632 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-03 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 21 of the BRCA2 gene. It is expected to disrupt RNA 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 in many families with a history of breast and/or ovarian cancer (PMID: 24156927, 18489799), and observed to segregate with disease in two families (PMID: 9971877). ClinVar contains an entry for this variant (Variation ID: 38183) Experimental studies have shown that this variant disrupts splicing of exon 22 (PMID: 9971877, 23451180, 25382762). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131043 SCV000185973 pathogenic Hereditary cancer-predisposing syndrome 2018-10-05 criteria provided, single submitter clinical testing The c.8755-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 21 of the BRCA2 gene. This alteration has been identified in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Machackova E et al. BMC Cancer. 2008 May;8:140; Tea MK et al. Maturitas. 2014 Jan;77:68-72; Goidescu IG et al. Clujul Med, 2018 Apr;91:157-165). This alteration has also been reported in 1 of 1296 individuals with pancreatic adenocarcinoma (Dudley B et al. Cancer, 2018 Apr;124:1691-1700). In two separate studies, mRNA transcript analysis and minigene assays revealed aberrant transcripts that can lead to a frameshift as the result of this alteration (Colombo M et al. PLoS ONE. 2013 Mar;8(2):e57173; Acedo A et al. Hum. Mutat. 2015 Feb;36(2):210-21). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Counsyl RCV000031766 SCV000220669 likely pathogenic Breast-ovarian cancer, familial 2 2014-09-03 criteria provided, single submitter literature only
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000220836 SCV000271337 pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-22 criteria provided, single submitter clinical testing The c.8755-1G>A variant in BRCA2 has been reported in at least 10 individuals wi th BRCA2-associated cancers and segregated with disease in 3 affected relatives from 3 families (Wagner 1999, Machackova 2008, Breast Cancer Information Core da tabase, www.research.nhgri.nih.gov/bic/). It was absent from large population st udies. This variant occurs in the invariant region (+/- 1,2) of the splice conse nsus sequence and in vitro studies indicate that this variant results in skippin g of exon 22, leading to a premature stop codon and an abnormal or absent protei n (Machackova 2008, Colombo 2013). Heterozygous loss of function of the BRCA2 ge ne is an established disease mechanism in hereditary breast and ovarian cancer ( HBOC). In summary, this variant meets our criteria to be classified as pathogeni c for HBOC in an autosomal dominant manner based upon the predicted impact to th e protein, segregation studies, and prevalence in affected individuals.
GeneKor MSA RCV000238986 SCV000296836 likely pathogenic not specified 2016-07-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031766 SCV000327961 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Mendelics RCV000220836 SCV000838885 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131043 SCV000906954 pathogenic Hereditary cancer-predisposing syndrome 2021-01-29 criteria provided, single submitter clinical testing This variant causes a G to A nucleotide substitution at the canonical -1 position of intron 21 splice acceptor site of the BRCA2 gene. This variant is also known as IVS21-1G>A in the literature. Functional RNA studies have shown that this variant causes skipping of exon 22 or skipping of exon 22 plus first 51 nucleotides of exon 23 (PMID: 9971877, 18489799, 23451180, 25382762). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over fifteen individuals affected with breast and/or ovarian cancer (PMID: 9971877, 11802209, 18489799, 29785153, 32206145, 32438681; Matteis 2019, DOI: 10.12892/ejgo5165.2019) and in an individual affected with pancreatic and prostate cancer with family history of breast and/or ovarian cancer (PMID: 29360161). This variant has also been reported in 26 individuals from 13 different families at high risk for breast cancer (PMID: 24156927). 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 RCV000220836 SCV000918928 pathogenic Hereditary breast and ovarian cancer syndrome 2017-09-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8755-1G>A variant involves the alteration of a conserved intronic nucleotide and 3/5 splice prediction tools predict a significant impact on normal splicing. A functional study, Colombo_2013, shows the variant to produce two aberrant transcripts, skipping of exon 22 (resulting in p.Gly2919LeufsX3) and skipping of exon 22 + 51 bp at the 5' end of exon 23 (resulting in p.Gly2919LysfsX26). This variant is absent in 244786 control chromosomes (gnomAD). A publication, Tea_2014, reports the variant in 26 affected individuals from 13 families. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "Pathogenic." Taken together, this variant is classified as pathogenic.
Mendelics RCV000031766 SCV001139232 likely pathogenic Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000031766 SCV001367313 pathogenic Breast-ovarian cancer, familial 2 2019-12-23 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PS3,PM2.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000031766 SCV001434912 pathogenic Breast-ovarian cancer, familial 2 2019-02-05 criteria provided, single submitter clinical testing This c.8755-1G>A variant in the BRCA2 gene has been shown to alter mRNA splicing and is predicted to introduce a premature translation termination codon (PMID 18489799, 23451180, 25382762). This variant has been reported in multiple families affected with hereditary breast and ovarian cancer (PMID 18489799, 24156927) and has never been observed in general population databases. Therefore, the c.8755-1G>A variant is classified as pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310186 SCV001499781 pathogenic Breast-ovarian cancer, familial 1 2020-04-02 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642490 SCV001854419 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
Sharing Clinical Reports Project (SCRP) RCV000031766 SCV000054374 likely pathogenic Breast-ovarian cancer, familial 2 2011-04-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031766 SCV000147452 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Division of Human Genetics,Medical University Innsbruck RCV000031766 SCV000212032 pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000220836 SCV000587969 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357980 SCV001553596 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 c.8755-1G>A variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSNP (ID: rs81002812) as With Likely pathogenic, Pathogenic allele, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, BIC; classified as likely pathogenic by SCRP, Counsyl; classified as uncertain significance by ENIGMA ), Clinvitae (conflicting interpretations of pathogenicity), Genesight-COGR, LOVD 3.0 , UMD-LSDB (2X causal), BIC Database (6X clinically important), ARUP Laboratories (Definitely pathogenic), databases. The variant was not identified in Zhejiang Colon Cancer Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.8755-1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Several functional studies using splicing assays demonstrated the variant result in aberrant transcripts and considered as deleterious mutations (Acedo 2015, Machackova 2008). mRNA Transcript Analysis in in vitro study by Colombo (2012) showed skipping of exon 22 in one case and skipping of exon 22+51 bp at the 59-end of exon 23 in another. In the same study, cDNA sequence analyses revealed maintenance of the constitutional heterozygosity for c.9876G>A synonymous change (exon 27), indicating expression of the normal mRNA from both the wild-type and mutated alleles. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
CZECANCA consortium RCV001391220 SCV001593136 pathogenic Carcinoma of pancreas 2021-03-04 no assertion criteria provided case-control
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001529355 SCV001742648 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV001529355 SCV001959477 pathogenic not provided no assertion criteria provided clinical testing

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