ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5090G>A (p.Cys1697Tyr) (rs397507241)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129997 SCV000184821 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,Structural Evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501879 SCV000591578 uncertain significance not specified 2013-05-08 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735461 SCV000863598 uncertain significance Breast and/or ovarian cancer 2013-03-15 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000501879 SCV000916752 uncertain significance not specified 2018-06-05 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5090G>A (p.Cys1697Tyr) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246440 control chromosomes. c.5090G>A has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer. However, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating transcriptional activity, which indicated that the variant abolishes normal transcription (Woods_2016). However, this assay was performed using a partial BRCA1 protein in HEK293 cells, rather than the tissue of interest, which may not accurately reflect clinical significance. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000464859 SCV000549322 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-09-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 1697 of the BRCA1 protein (p.Cys1697Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 24729269). ClinVar contains an entry for this variant (Variation ID: 37635). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000031216 SCV000053816 uncertain significance Breast-ovarian cancer, familial 1 2011-12-09 no assertion criteria provided clinical testing

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