ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2021C>G (p.Pro674Arg) (rs876660543)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215962 SCV000278064 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000484472 SCV000570804 uncertain significance not provided 2016-06-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2021C>G at the cDNA level, p.Pro674Arg (P674R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). Using alternate nomenclature, this variant would be defined as BRCA1 2140C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Pro674Arg 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 Proline and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Pro674Arg occurs at a position that is not conserved and is located within the DNA binding domain as well as a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Pro674Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000695958 SCV000824499 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-02-13 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 674 of the BRCA1 protein (p.Pro674Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. 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: 233643). 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 tolerated, 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.

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