ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4951T>C (p.Ser1651Pro) (rs879254042)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586097 SCV000293269 uncertain significance not provided 2015-10-23 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4951T>C at the cDNA level, p.Ser1651Pro (S1651P) at the protein level, and results in the change of a Serine to a Proline (TCC>CCC). Using alternate nomenclature, this variant would be defined as BRCA1 5070T>C. This variant has been evaluated in a cisplatin response based functional assay but yielded ambivalent results (Bouwman 2013). BRCA1 Ser1651Pro 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 Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser1651Pro occurs at a position that is conserved in mammals and is located in the BRCT1 and DNA binding domains as well as a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser1651Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574641 SCV000673066 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000586097 SCV000699184 uncertain significance not provided 2017-05-18 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4951T>C (p.Ser1651Pro) variant located in the BRCT domain (InterPro) involves the alteration of a conserved nucleotide and 5/5 in silico tools predict damaging outcome for this variant and structural analysis is also consistent with such outcome (Karchin_2007). This variant is absent in 121406 control chromosomes from ExAC and has also not been reported in affected individuals in the literature to our knowledge. One clinical diagnostic laboratory has classified this variant as "uncertain significance," without evidence to independently evaluate. The variant was assessed for its ability to functionally complement BRCA1-deficient mouse embryonic stem cells, however, results for this variant were ambivalent (Bouwman_2013). Another missense change at the same residue, p.S1651F, has been reported once by BIC and is classified as uncertain significance by a laboratory in ClinVar. Thus, this variant is currently classified as a "Variant of Uncertain Significance (VUS)," due to lack of sufficient clinical and functional studies at this time.

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