ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5522G>C (p.Ser1841Thr) (rs80357368)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480419 SCV000572675 uncertain significance not provided 2017-01-06 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5522G>C at the cDNA level, p.Ser1841Thr (S1841T) at the protein level, and results in the change of a Serine to a Threonine (AGT>ACT). Using alternate nomenclature, this variant would be defined as BRCA1 5641G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ser1841Thr 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 Threonine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ser1841Thr occurs at a position that is conserved in mammals and is located in the BRCT 2 Domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). 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 Ser1841Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000692105 SCV000819913 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-10 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 1841 of the BRCA1 protein (p.Ser1841Thr). The serine residue is highly conserved and there is a small physicochemical difference between serine and threonine. 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: 423044). 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 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 RCV000775939 SCV000910437 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-12 criteria provided, single submitter clinical testing

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