ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.891_899delinsGATACTTCAG (p.Thr298fs) (rs276174914)

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Total submissions: 10
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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) RCV000112859 SCV000783805 pathogenic Breast-ovarian cancer, familial 2 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000160265 SCV000210709 pathogenic not provided 2018-06-05 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted BRCA2 c.891_899delAACAGTTGTinsGATACTTCAG at the cDNA level and p.Thr298IlefsX7 (T298IfsX7) at the protein level. The surrounding sequence is ATGA[delAACAGTTGT][insGATACTTCAG]AGAT. The variant causes a frameshift, which changes a Threonine to an Isoleucine at codon 298, and creates a premature stop codon at position 7 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.891_899delAACAGTTGTinsGATACTTCAG, also known as 1119del9ins10 using alternative nomenclature, has been reported in at least two individuals with breast cancer (Malone 2006, Susswein 2016). We consider this variant to be pathogenic.
Ambry Genetics RCV000218535 SCV000277017 pathogenic Hereditary cancer-predisposing syndrome 2015-06-26 criteria provided, single submitter clinical testing
Invitae RCV000461715 SCV000549682 pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr298Ilefs*7) 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 an individual with breast cancer (PMID: 26681312), as well as several individuals in the Breast Cancer Information Core database (PMID: 10923033). This variant is also known as c.891_899delAACAGTTGTinsGATACTTCAG in the literature. ClinVar contains an entry for this variant (Variation ID: 125928). A different variant (c.893_899delCAGTTGTinsTACTTCAG) giving rise to the same protein effect observed here (p.Thr298Ilefs*7) has been reported in an individual affected with breast and ovarian cancer (PMID: 27798748), indicating that this residue may be critical for protein function. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Molecular Medicine,Queen's University RCV000461715 SCV000588073 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769683 SCV000901096 pathogenic Breast and/or ovarian cancer 2017-05-08 criteria provided, single submitter clinical testing
Color RCV000218535 SCV000905001 pathogenic Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000461715 SCV000918927 pathogenic Hereditary breast and ovarian cancer syndrome 2018-06-15 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.891_899delinsGATACTTCAG (p.Thr298IlefsX7) 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 (eg., p.Asn319fsX8 and p.Lys343fsX6). The variant was absent in 235816 control chromosomes. c.891_899delinsGATACTTCAG has been reported in the literature and reputable databases in individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112859 SCV000145784 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 RCV000461715 SCV000587574 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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