ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4997dup (p.Tyr1666Ter) (rs876658947)

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Total submissions: 6
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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 2018-09-20 criteria provided, single submitter clinical testing The c.4997dupA pathogenic mutation, located in coding exon 15 of the BRCA1 gene, results from a duplication of A at nucleotide position 4997, causing a translational frameshift with a predicted alternate stop codon. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Invitae RCV000499541 SCV001223548 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1666*) in the BRCA1 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 not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 231083). Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000660911 SCV000591560 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The p.Tyr1666X variant has not been previously identified in the literature. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence leading to a premature stop codon at codon 1666 of BRCA1. This alteration is predicted to lead to a truncated or absent protein and loss of function. Loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast cancer patients. In summary, based on the above information, this variant is classified as pathogenic.

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