ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3680_3681del (p.Leu1227fs) (rs80359395)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131092 SCV000186022 pathogenic Hereditary cancer-predisposing syndrome 2017-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Breast Cancer Information Core (BIC) (BRCA2) RCV000077311 SCV000146276 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131092 SCV000683571 pathogenic Hereditary cancer-predisposing syndrome 2016-09-25 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077311 SCV000326893 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077311 SCV000488074 pathogenic Breast-ovarian cancer, familial 2 2016-02-17 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077311 SCV000282380 pathogenic Breast-ovarian cancer, familial 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000214590 SCV000278846 pathogenic not provided 2018-01-26 criteria provided, single submitter clinical testing This deletion of two nucleotides in BRCA2 is denoted c.3680_3681delTG at the cDNA level and p.Leu1227GlnfsX5 (L1227QfsX5) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAC[delTG]AATG. The deletion causes a frameshift, which changes a Leucine to a Glutamine at codon 1227, and creates a premature stop codon at position 5 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.3680_3681delTG, previously reported as 3908delTG, has been observed in association with early onset breast and ovarian cancer (Peto 1999, Risch 2001, Pal 2014, Song 2014). We consider this variant to be pathogenic.
Genologica Medica RCV000077311 SCV000577951 pathogenic Breast-ovarian cancer, familial 2 2017-01-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000044241 SCV000916870 pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-20 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3680_3681delTG (p.Leu1227GlnfsX5) 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.3689delC [p.Ser1230fsX9] and c.3744_3747delTGAG [p.Ser1248fsX10]). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/30950 control chromosomes at a frequency of 0.0000323, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been identified in numerous HBOC patients reported in the literature (e.g., Lecarpentier_2012, Miramar_2008, Pal_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000044241 SCV000072254 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu1227Glnfs*5) 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 individuals and families affected with breast and/or ovarian cancer (PMID: 24013928, 11179017, 24916970, 24728189, 22762150, 26845104), and colorectal cancer (PMID: 27356891). This variant is also known as 3908_3909delTG in the literature. ClinVar contains an entry for this variant (Variation ID: 51504). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000044241 SCV000605793 pathogenic Hereditary breast and ovarian cancer syndrome 2016-10-04 criteria provided, single submitter clinical testing The p.Leu1227fs variant in BRCA2 has been reported in at least 8 individuals wit h BRCA2-associated cancers (Peto 1999, Risch 2001, Pal 2014, Breast Cancer Infor mation Core (BIC) database). This variant was absent from large population studi es, though the ability of these studies to accurately detect indels may be limit ed. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 1227 and leads to a premature terminat ion codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBO C). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282380.1). In summary, t his variant meets our criteria to be classified as pathogenic for HBOC in an aut osomal dominant manner based upon the predicted impact to the protein.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077311 SCV000296638 pathogenic Breast-ovarian cancer, familial 2 2015-08-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000214590 SCV000889026 pathogenic not provided 2015-08-07 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044241 SCV000587676 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077311 SCV000109108 pathogenic Breast-ovarian cancer, familial 2 2013-03-12 no assertion criteria provided clinical testing

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