ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1189_1190insTTAG (p.Gln397fs) (rs397515635)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131278 SCV000186246 pathogenic Hereditary cancer-predisposing syndrome 2017-11-01 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)
Color RCV000131278 SCV000688698 pathogenic Hereditary cancer-predisposing syndrome 2017-03-24 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000238897 SCV000326510 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000238897 SCV000489480 pathogenic Breast-ovarian cancer, familial 2 2016-10-10 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000043755 SCV000588077 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000238897 SCV000323962 pathogenic Breast-ovarian cancer, familial 2 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Integrated Genetics/Laboratory Corporation of America RCV000043755 SCV000694518 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-19 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.1189_1190insTTAG (p.Gln397Leufs) 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.1257delT/p.Cys419fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120790 control chromosomes. This variant has been reported in multiple affected individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000043755 SCV000071768 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-29 criteria provided, single submitter clinical testing This sequence change inserts 4 nucleotides in exon 10 of the BRCA2 mRNA (c.1189_1190insTTAG), causing a frameshift at codon 397. This creates a premature translational stop signal (p.Gln397Leufs*25) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with breast or ovarian cancer (PMID: 16644204, 22006311, 26787237, 26681312). This variant is also known as 1417insTTAG and 1418insTTAG in the literature. For these reasons, this sequence change has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000043755 SCV000605807 pathogenic Hereditary breast and ovarian cancer syndrome 2016-12-23 criteria provided, single submitter clinical testing The p.Gln397fs variant in BRCA2 has been reported in at least 5 individuals with BRCA2-associated cancers (Lalloo 2006, Walsh 2011, Susswein 2015, Breast Cancer Information Core (BIC) database), and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein?s ami no acid sequence beginning at position 397 and leads to a premature termination codon 25 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 (HBOC). In addition, this variant was classified as Pathogenic on October 18, 2016 by t he ClinGen-approved ENIGMA expert panel (ClinVar SCV000323962.1). In summary, th is variant meets criteria to be classified as pathogenic for HBOC in an autosoma l dominant manner.
PreventionGenetics RCV000679153 SCV000805648 pathogenic not provided 2017-11-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000238897 SCV000296621 pathogenic Breast-ovarian cancer, familial 2 2015-08-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679153 SCV000887751 pathogenic not provided 2015-08-21 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000043755 SCV000587582 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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