ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9253dupA (p.Thr3085Asnfs) (rs80359752)

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Total submissions: 22
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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) RCV000031808 SCV000301365 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 RCV000195407 SCV000073773 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr3085Asnfs*26) 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 and families affected with breast, ovarian, and prostate cancer (PMID: 11389159, 16455195, 16683254, 19656164, 21952622, 22798144, 23569316, 25330149). This variant is also known as 9474insA, 9481insA, 9253insA, and c.9253_9254insA in the literature. ClinVar contains an entry for this variant (Variation ID:38225). 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 RCV000130780 SCV000185673 pathogenic Hereditary cancer-predisposing syndrome 2018-05-29 criteria provided, single submitter clinical testing The c.9253dupA pathogenic mutation, located in coding exon 23 of the BRCA2 gene, results from a duplication of A at nucleotide position 9253, causing a translational frameshift with a predicted alternate stop codon (p.T3085Nfs*26). This alteration has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Pal T et al. Cancer. 2015 Dec;121:4173-80). This mutation has also been detected in a male with early-onset prostate cancer (Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;1051230-4) and in a male breast cancer patient (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586). Of note, this alteration is also designated as c.9253insA, c.9253_9254insA, and c.9474insA 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 RCV000045760 SCV000210800 pathogenic not provided 2018-12-26 criteria provided, single submitter clinical testing This duplication of one nucleotide in BRCA2 is denoted c.9253dupA at the cDNA level and p.Thr3085AsnfsX26 (T3085NfsX26) at the protein level. The normal sequence, with the bases that are duplicated in braces, is GAAAAAA[A]CAGG. The duplication causes a frameshift, which changes a Threonine to an Asparagine at codon 3085, and creates a premature stop codon at position 26 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.9253dupA, also known as BRCA2 9481insA, 9481dupA and 9474insA using alternate nomenclature, has been observed in association with breast, ovarian and prostate cancer (Montagna 2002, Spearman 2008, Borg 2010, Kote-Jarai 2011, Kim 2012, Castro 2013, Kang 2015, Pal 2015). We consider this variant to be pathogenic.
Counsyl RCV000031808 SCV000220419 likely pathogenic Breast-ovarian cancer, familial 2 2014-06-16 criteria provided, single submitter literature only
Color Health, Inc RCV000130780 SCV000292174 pathogenic Hereditary cancer-predisposing syndrome 2020-08-03 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 24 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as c,9246_9247insA, c.9253dup and 9481insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 2/243602 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 RCV000031808 SCV000296685 pathogenic Breast-ovarian cancer, familial 2 2015-04-15 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031808 SCV000328084 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000031808 SCV000575733 pathogenic Breast-ovarian cancer, familial 2 2015-10-23 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000195407 SCV000588127 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000031808 SCV000605645 pathogenic Breast-ovarian cancer, familial 2 2015-07-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000195407 SCV000695224 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-14 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9253dupA (p.Thr3085AsnfsX26) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant allele was found at a frequency of 4e-06 in 248942 control chromosomes. c.9253dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Bergthorsson_2001, Inoue_1997, Kim_2012, Pal_2015, Rebbeck_2016). These data indicate that the variant is very likely to be associated with disease. At-least one trans heterozygous co-occurrence with another pathogenic variant has been reported (BRCA1 c.3226_3227AG (reported as NM_007294:c.3228_3229delAG), p.Gly1077fs) (Rebbeck_2016). Thirteen clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031808 SCV000744559 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000031808 SCV000839929 pathogenic Breast-ovarian cancer, familial 2 2018-04-27 criteria provided, single submitter clinical testing The c.9246_9247dupA (p.Thr3085Asnfs*26) frameshift variant in BRCA2 has been reported in multiple unrelated patients with breast, ovarian or prostate cancer [PMID 11389159, 16455195, 16683254, 21952622,22798144, 25330149]. Based on the current evidence, this variant is classified as pathogenic
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000045760 SCV000889181 pathogenic not provided 2015-04-15 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031808 SCV000054416 pathogenic Breast-ovarian cancer, familial 2 2012-12-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031808 SCV000147581 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 RCV000195407 SCV000587992 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031808 SCV000733335 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Gharavi Laboratory,Columbia University RCV000045760 SCV000809461 pathogenic not provided 2018-09-16 no assertion criteria provided research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785231 SCV000923799 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045760 SCV001554114 pathogenic not provided no assertion criteria provided clinical testing The BRCA2 p.Thr3085AsnfsX26 variant was identified in 13 of 20330 proband chromosomes (frequency: 0.0006) from German, Danish, Korean, American, and British individuals or families with (sporadic, high risk, early onset, or male) breast cancer, sporadic or familial ovarian cancer or prostate cancer (Meindl_2002_11802209, Bergthorsson_2001_11389159, Kang_2015_25863477 , Kim_2012_22798144, Pal_2015_26287763 , Pritzlaff_2016_28008555, Kote-Jarai_2011_21952622, Rebbeck_2016_27836010, Borg_2010_20104584, Cybulski_2015_25330149). In a study looking at transheterozygosity (inheritance of pathogenic mutations in both BRCA1 and BRCA2), the variant was identified in 1 Italian proband with breast cancer, co-occurring with BRCA1 c.3228_3229delAG (Rebbeck_2016_27836010). The variant was also identified in dbSNP (ID: rs80359752) “With Pathogenic allele”, ClinVar (classified pathogenic, reviewed by an expert panel (2016); submitters: pathogenic by ENIGMA, CIMBA, Fulgent Genetics, Ambry Genetics, GeneDx, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, Invitae, Dept. of Medical Genetics (Oslo University Hospital), BIC and SCRP (Sharing Clinical Reports Project); and likely pathogenic by Counsyl), Clinvitae (4x), GeneInsight-COGR (classified pathogenic by 2 clinical laboratories), LOVD 3.0 (1x), UMD-LSDB (5x causal), BIC Database (19x, with clinical importance, class 5 (pathogenic)), ARUP Laboratories (5-definitely pathogenic), Zhejiang Colon Cancer Database; the variant was not identified in Cosmic, MutDB, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.9253dupA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3085 and leads to a premature stop codon at position 3110. 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.

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