ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2830T>A (p.Cys944Ser) (rs1064795603)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484974 SCV000571577 uncertain significance not provided 2016-09-01 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2830T>A at the cDNA level, p.Cys944Ser (C944S) at the protein level, and results in the change of a Cysteine to a Serine (TGT>AGT). Using alternate nomenclature, this variant would be defined as BRCA1 2949T>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Cys944Ser 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 Cysteine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Cys944Ser occurs at a position that is not conserved and is located in the DNA binding domain and the region of interaction with RAD51 (Chen 1998, Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Cys944Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000525415 SCV000635869 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-10-04 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 944 of the BRCA1 protein (p.Cys944Ser). The cysteine residue is moderately conserved and there is a moderate physicochemical difference between cysteine and serine. 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: 422172). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Color RCV000775950 SCV000910454 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-09 criteria provided, single submitter clinical testing

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