ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7366C>T (p.Gln2456Ter) (rs397507912)

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Total submissions: 7
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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) RCV000257405 SCV000324541 pathogenic Breast-ovarian cancer, familial 2 2016-10-18 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics RCV000220866 SCV000277713 pathogenic Hereditary cancer-predisposing syndrome 2017-06-01 criteria provided, single submitter clinical testing The p.Q2456* pathogenic mutation (also known as c.7366C>T), located in coding exon 13 of the BRCA2 gene, results from a C to T substitution at nucleotide position 7366. This changes the amino acid from a glutamine to a stop codon within coding exon 13. 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000257405 SCV000327641 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000257405 SCV000677839 likely pathogenic Breast-ovarian cancer, familial 2 2017-02-10 criteria provided, single submitter clinical testing
Invitae RCV000637747 SCV000759221 pathogenic Hereditary breast and ovarian cancer syndrome 2020-03-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln2456*) 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 in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 233359). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000637747 SCV001362829 pathogenic Hereditary breast and ovarian cancer syndrome 2019-06-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7366C>T (p.Gln2456X) 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 (e.g. c.7379_7380insG (p.Asn2460fsX15), c.7419_7420delTG (p.Cys2473X), c.7480C>T (p.Arg2494X)). The variant was absent in 251108 control chromosomes (gnomAD). c.7366C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other submitters, including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (4x; including the expert panel) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000257405 SCV001434857 pathogenic Breast-ovarian cancer, familial 2 2018-10-08 criteria provided, single submitter clinical testing The c.7366C>T (p.Glu2456*) variant in the BRCA2 gene is predicted to introduce a premature translation termination codon, which is predicted to result in nonsense-mediated mRNA decay, which has been reported as the disease causing mechanism of BRCA2 related disorders [PMID: 20104584]. This variant is absent from large databases of genetic variation in the general population. Therefore, the c.7366C>T (p.Glu2456*) variant in the BRCA2 gene is classified as pathogenic.

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