ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5609_5610delinsAG (p.Phe1870Ter) (rs276174859)

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Total submissions: 13
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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) RCV000113449 SCV000300904 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 RCV000044694 SCV000072707 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe1870*) 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 reported in several individuals with a personal or family history of breast and/or ovarian cancer (PMID: 22729890, 24156927, 22923021, 21232165) and as compound heterozygous in individuals with Fanconi anemia (PMID: 12065746). This variant is also known as 5837 TC to AG in the literature. ClinVar contains an entry for this variant (Variation ID: 51890). 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 RCV000129595 SCV000184379 pathogenic Hereditary cancer-predisposing syndrome 2018-06-05 criteria provided, single submitter clinical testing The c.5609_5610delTCinsAG pathogenic mutation (also known as p.F1870*), located in coding exon 10 of the BRCA2 gene, results from an in-frame deletion of TC and insertion of AG at nucleotide positions 5609 to 5610. This changes the amino acid from a phenylalanine to a stop codon within coding exon 10. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date (Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Becker AA et al. Breast Cancer Res. Treat. 2012 Aug;135:167-75; Tea MK et al. Maturitas 2014 Jan;77:68-72; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238), and in an individual with Fanconi Anemia (Howlett NG et al. Science 2002 Jul;297:606-9). Of note, this alteration is also designated as 5837TC>AG 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.
Ambry Genetics RCV000214770 SCV000277016 pathogenic Tumor susceptibility linked to germline BAP1 mutations 2015-06-29 criteria provided, single submitter clinical testing The c.5609_5610delTCinsAG pathogenic mutation (also known as p.F1870* and 5837TC>AG), located in coding exon 10 of the BRCA2 gene, results from the deletion and insertion of 2 nucleotides at positions 5609 and 5610. This changes the amino acid at codon 1870 from a phenylalanine to a stop codon. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date (Stegel et al. BMC Med Genet. 2011 Jan 14;12:9; Becker et al. Breast Cancer Res Treat. 2012 Aug;135(1):167-75; Tea MK et al. Maturitas. 2014 Jan;77(1):68-72) and in an individual with Fanconi Anemia (Howlett et al. Science. 2002 Jul 26;297(5581):606-9). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000113449 SCV000296598 pathogenic Breast-ovarian cancer, familial 2 2015-10-17 criteria provided, single submitter clinical testing
GeneDx RCV000255347 SCV000321470 pathogenic not provided 2018-10-15 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted BRCA2 c.5609_5610delTCinsAG at the cDNA level and p.Phe1870Ter (F1870X) at the protein level. The surrounding sequence is AGTT[delTC][insAG]AGTA. The deletion and insertion creates a nonsense variant, which changes a Phenylalanine to a premature stop codon (TTC>TAG). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.5609_5610delTCinsAG, previously reported as BRCA2 5837delTCinsAG using alternate nomenclature, has been seen in several families with Hereditary Breast and Ovarian Cancer syndrome (van der Hout 2006, Stegel 2011, Becker 2012, Novakovic 2012, Tea 2014, Meisel 2017). It has also been seen in the compound heterozygous state with a BRCA2 missense variant in a patient with Fanconi Anemia (Howlett 2002). This variant is considered to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113449 SCV000327242 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129595 SCV000683714 pathogenic Hereditary cancer-predisposing syndrome 2015-09-22 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000255347 SCV000805727 pathogenic not provided 2017-03-21 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000113449 SCV001369847 pathogenic Breast-ovarian cancer, familial 2 2020-03-05 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310124 SCV001499672 pathogenic Breast-ovarian cancer, familial 1 2020-04-02 criteria provided, single submitter clinical testing
OMIM RCV000009924 SCV000030145 pathogenic Fanconi anemia, complementation group D1 2002-07-26 no assertion criteria provided literature only
Breast Cancer Information Core (BIC) (BRCA2) RCV000113449 SCV000146643 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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