ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4997dup (p.Tyr1666Ter) (rs876658947)

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Total submissions: 5
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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) RCV000660911 SCV000783147 pathogenic Breast-ovarian cancer, familial 1 2017-12-15 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000159928 SCV000210053 pathogenic not provided 2016-06-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.4997dupA at the cDNA level and p.Tyr1666Ter (Y1666X) at the protein level. Using alternate nomenclature this variant would be defined as BRCA1 5116dupA. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>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, the adjacent variant BRCA1 c.4998C>A, which also results in a premature stop codon at this residue (p.Tyr1666Ter), has been reported in an individual with breast cancer (Lecarpentier 2012). We therefore consider BRCA1 c.4997dupA to be pathogenic.
Ambry Genetics RCV000220908 SCV000274825 pathogenic Hereditary cancer-predisposing syndrome 2016-11-11 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)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000499541 SCV000591560 pathogenic Hereditary breast and ovarian cancer syndrome 2012-05-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000499541 SCV000918718 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-10-05 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4997dupA (p.Tyr1666X) variant involves the duplication of an adenine nucleotide resulting in a premature stop codon. Truncating variants downstream of the variant of interest have been assessed as pathogenic by our laboratory (e.g., c.5289delG [p.Leu1764fsX1] and c.5335delC [p.Gln1779fsX14]). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 246126 control chromosomes. Multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.

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