ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.302A>G (p.Tyr101Cys) (rs587781798)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130062 SCV000184889 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000236777 SCV000293183 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.302A>G at the cDNA level, p.Tyr101Cys (Y101C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). Using alternate nomenclature, this variant would be defined as BRCA1 421A>G. This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. BRCA1 Tyr101Cys was not observed in large population cohorts (Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Tyr101Cys is located in the BRD7 interaction domain (Harte 2010). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Tyr101Cys is a pathogenic or benign variant.
Color RCV000130062 SCV000909415 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Invitae RCV000797186 SCV000936732 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-13 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 101 of the BRCA1 protein (p.Tyr101Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. 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: 141504). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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