ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4284dup (p.Gln1429fs) (rs80359439)

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Total submissions: 20
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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) RCV000031473 SCV000300733 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000044387 SCV000072400 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1429Serfs*9) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and ovarian cancer (PMID: 11179017, 20373018, 22085629, 24156927, 24728189). This variant is also known as 4510insT and 4512insT in the literature. ClinVar contains an entry for this variant (Variation ID: 37892). 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 RCV000130074 SCV000184901 pathogenic Hereditary cancer-predisposing syndrome 2019-04-16 criteria provided, single submitter clinical testing The c.4284dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 4284, causing a translational frameshift with a predicted alternate stop codon (p.Q1429Sfs*9). This mutation has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Koumpis C et al. Hered Cancer Clin Pract. 2011;9:10; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Labidi-Galy SI et al. Clin. Cancer Res. 2018 01;24:326-333; Marchetti C et al. Ann. Surg. Oncol. 2018 Nov;25:3701-3708; Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620), an individual with prostate cancer (Pilie PG et al. Cancer. 2017 Oct;123(20):3925-3932), and one individual with medulloblastoma diagnosed in infancy (Waszak SM et al. Lancet Oncol. 2018 06;19:785-798). Of note, this alteration is also designated as 4512insT and 4510insT 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.
GeneDx RCV000160287 SCV000210748 pathogenic not provided 2019-01-17 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.4284dupT at the cDNA level and p.Gln1429SerfsX9 (Q1429SfsX9) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ATTTTT[dupT]CAGA. The duplication causes a frameshift, which changes a Glutamine to a Serine at codon 1429, and creates a premature stop codon at position 9 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.4284dupT, previously reported as 4510insT or 4512insT using alternate nomenclature, has been observed in association with breast and ovarian cancer (Risch 2001, Zuradelli 2010, Koumpis 2011, Song 2014, Tea 2014). We consider this variant to be pathogenic.
Counsyl RCV000031473 SCV000220993 likely pathogenic Breast-ovarian cancer, familial 2 2014-12-29 criteria provided, single submitter literature only
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000044387 SCV000271327 pathogenic Hereditary breast and ovarian cancer syndrome 2016-02-08 criteria provided, single submitter clinical testing The p.Gln1429fs variant in BRCA2 has been reported in >10 individuals with BRCA2 -associated cancers (Risch 2001, Zuradelli 2010, Zhang 2011, Koumpis 2011, Caux- Moncoutier 2011, Song 2014, Breast Cancer Information Core (BIC) database) and w as absent from large population studies. This variant is predicted to cause a fr ameshift, which alters the protein?s amino acid sequence beginning at position 1 429 and leads to a premature termination codon 9 amino acids downstream. This al teration is then predicted to lead to a truncated or absent protein. Heterozygou s loss of function of the BRCA2 gene is an established disease mechanism in here ditary breast and ovarian cancer (HBOC). In addition, this variant was classifie d as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Clin Var SCV000300733.2). In summary, this variant meets our criteria to be classifie d as pathogenic for HBOC in an autosomal dominant manner.
Color Health, Inc RCV000130074 SCV000292168 pathogenic Hereditary cancer-predisposing syndrome 2020-09-09 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 and/or ovarian cancer (PMID: 11179017, 20373018, 21324516, 22085629, 24156927, 27741520). This variant has also been identified in 1/244426 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 RCV000160287 SCV000296728 pathogenic not provided 2020-01-14 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 patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031473 SCV000327007 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneKor MSA RCV000044387 SCV000693567 pathogenic Hereditary breast and ovarian cancer syndrome 2020-01-01 criteria provided, single submitter clinical testing This sequence change inserts one nucleotide in exon 11 of the BRCA2 mRNA (c.4284dupT), causing a frameshift after codon 1429 and the creation of a premature translation stop signal 9 amino acid residues later p.(Gln1429Serfs*9). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant is also known as 4510insT and 4512insT in the international literature and has been reported in individuals affected with breast and ovarian cancer (PMID: 11179017, 20373018, 22085629, 24156927, 24728189). The mutation database ClinVar contains entries for this variant (Variation ID: 37892).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044387 SCV000694762 pathogenic Hereditary breast and ovarian cancer syndrome 2017-03-07 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4284dupT (p.Gln1429Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.4398_4402delACATT [p.Leu1466fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent from the large control population database ExAC (0/122560 control chromosomes). Several publications have identified the variant in affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases have cited this variant in patients and have classified it as pathogenic. Taken together, this variant is classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000031473 SCV000839927 pathogenic Breast-ovarian cancer, familial 2 2018-01-30 criteria provided, single submitter clinical testing This c.4284_4285insT (p.Gln1429Serfs*9) variant in the BRCA2 gene has been reported in multiple breast cancer and ovarian cancer patient [PMID: 21120943, 22085629, 24728189] while only observed once in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidences, this c.4284_4285insT (p.Gln1429Serfs*9) variant in the BRCA2 gene is classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000160287 SCV001248273 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285485 SCV001471920 pathogenic none provided 2020-03-22 criteria provided, single submitter clinical testing The BRCA2 c.4284dupT; p.Gln1429fs variant (rs1005805156) is reported in the literature in multiple individuals affected with breast or ovarian cancer or that met criteria for hereditary breast and/or ovarian cancer (HBOC) syndrome (Fernandes 2016, Koumpis 2011, Palmero 2018, Risch 2001, Zhang 2011, Zuradelli 2010). This variant is present on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37892). This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Fernandes GC et al. Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. Oncotarget. 2016 Dec 6;7(49):80465-80481. Koumpis C et al. Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Greece. Hered Cancer Clin Pract. 2011 Nov 15;9:10. Palmero EI et al. The germline mutational landscape of BRCA1 and BRCA2 in Brazil. Sci Rep. 2018 Jun 15;8(1):9188. Risch HA et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001 Mar;68(3):700-10. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. Zuradelli M et al. Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics. Breast Cancer Res Treat. 2010 Nov;124(1):251-8.
Mayo Clinic Laboratories, Mayo Clinic RCV000160287 SCV001716153 pathogenic not provided 2019-09-21 criteria provided, single submitter clinical testing PVS1, PS4_Mod, PM1, PM2, PP5
Sharing Clinical Reports Project (SCRP) RCV000031473 SCV000054078 pathogenic Breast-ovarian cancer, familial 2 2012-10-30 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031473 SCV000146401 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 RCV000044387 SCV000587708 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353482 SCV000591899 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Gln1429SerfsX9 variant was identified in 3 of 4408 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancers (Caux-Moncoutier 2011, Risch 2001, Terabeax 2014). The variant was identified by our laboratory in 1 individual who was unaffected at the time of testing. The variant was also identified in dbSNP (ID: rs80359439 “With pathogenic allele”. The p.Gln1429SerfsX9variant was identified in the Clinvar database and classified as pathogenic by Invitae, Ambry Genetics, GeneDx, BIC and Sharing clinical Reports project. Counsy classified the variant as likely pathogenic. In the BRCA Share UMD database, the variant was identified 14x and classified as causal. The variant was identified with a co-occurring pathogenic BRCA1 variant (c.5266dup (p.Gln1756ProfsX74). The BIC database identified the variant 4X with clinical importance and classified as pathogenic. The ARUP laboratory identified the variant 1x and classified it as pathogenic. The p.Gln1429SerfsX9 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1429 and leads to a premature stop codon 9 codons downstream. 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 hereditary breast and ovarian cancer 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.
CZECANCA consortium RCV001271036 SCV001451853 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing

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