ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3172A>T (p.Lys1058Ter) (rs730881521)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000162052 SCV000326829 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Division Human Genetics,Medical University Innsbruck RCV000162052 SCV000212015 pathogenic Breast-ovarian cancer, familial 2 2015-02-11 no assertion criteria provided clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000162052 SCV000300593 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 RCV000160058 SCV000210307 pathogenic not provided 2014-08-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.3172A>T at the cDNA level and p.Lys1058Ter (K1058X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic.
Invitae RCV000467920 SCV000549658 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1058 (p.Lys1058*) of the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular truncation has been reported in the literature in an individual affected with breast cancer (PMID: 26681312), as well as an individual with a personal and/or family history of breast/ovarian cancer (PMID: 24156927). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000467920 SCV000605798 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-15 criteria provided, single submitter clinical testing The p.Lys1058X variant in BRCA2 has been reported in 1 individual with a persona l or familial history of BRCA2-associated cancer (Tea 2014) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1058, which is predicted to lead to a truncated or absent pro tein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In addition, this vari ant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA e xpert panel (ClinVar SCV000300593). In summary, this variant meets criteria to b e classified as pathogenic for HBOC in an autosomal dominant manner based upon t he predicted impact to the protein.

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