ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3758C>G (p.Ser1253Cys) (rs397509100)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165814 SCV000216561 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000203862 SCV000260312 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 1253 of the BRCA1 protein (p.Ser1253Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 25036526). ClinVar contains an entry for this variant (Variation ID: 186252). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, 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.
Counsyl RCV000411367 SCV000488895 uncertain significance Breast-ovarian cancer, familial 1 2016-07-15 criteria provided, single submitter clinical testing
GeneDx RCV000759525 SCV000564736 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3758C>G at the cDNA level, p.Ser1253Cys (S1253C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). Using alternate nomenclature, this variant would be defined as BRCA1 3877C>G. This variant has been observed in at least one patient with ovarian cancer (Gleicher 2014). BRCA1 Ser1253Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser1253Cys is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA1 Ser1253Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000165814 SCV000683131 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759525 SCV000888896 uncertain significance not provided 2018-05-22 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000203862 SCV000586895 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-04-18 no assertion criteria provided clinical testing

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