ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1423A>T (p.Ser475Cys) (rs1064794047)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485151 SCV000567670 uncertain significance not provided 2016-04-26 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1423A>T at the cDNA level, p.Ser475Cys (S475C) at the protein level, and results in the change of a Serine to a Cysteine (AGC>TGC). Using alternate nomenclature, this variant would be defined as BRCA1 1542A>T. This variant has been observed in at least one individual with breast cancer (Flower 2015). BRCA1 Ser475Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser475Cys occurs at a position that is not conserved and is located in the DNA binding domain and a region known to interact with multiple proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Ser475Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000566059 SCV000661100 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000637344 SCV000758796 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-08-07 criteria provided, single submitter clinical testing This sequence change replaces serine with cysteine at codon 475 of the BRCA1 protein (p.Ser475Cys). 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 breast cancer, however, the germline status of the variant is unclear (PMID: 26727311). ClinVar contains an entry for this variant (Variation ID: 419692). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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