ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4222C>T (p.Gln1408Ter) (rs80358663)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215029 SCV000274248 pathogenic Hereditary cancer-predisposing syndrome 2017-05-03 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) RCV000031470 SCV000146393 pathogenic Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Color RCV000215029 SCV000903057 pathogenic Hereditary cancer-predisposing syndrome 2018-02-21 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031470 SCV000326991 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031470 SCV000300724 pathogenic Breast-ovarian cancer, familial 2 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000480509 SCV000567660 pathogenic not provided 2016-03-25 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.4222C>T at the cDNA level and p.Gln1408Ter (Q1408X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with breast cancer (Miolo 2009, Bayraktar 2012) and is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000044373 SCV000694754 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-18 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.4222C>T (p.Gln1408X) variant causes a nonsense mutation in exon 11 resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic/causal." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Invitae RCV000044373 SCV000072386 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1408*) 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 affected with breast cancer (PMID: 22009639, 19818148). This variant is also known as 4450C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 37889). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480509 SCV000600581 pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044373 SCV000587705 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031470 SCV000054075 pathogenic Breast-ovarian cancer, familial 2 2010-03-16 no assertion criteria provided clinical testing

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