ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5116G>A (p.Gly1706Arg) (rs886040864)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Molecular and Personalized Diagnostics,Institute of Biochemistry and Clinical Biochemistry, Teaching and Research Hospital Agostino Gemelli Foundation RCV000494689 SCV000579222 pathogenic Breast-ovarian cancer, familial 1 2015-02-05 criteria provided, single submitter phenotyping only We underline that this variant, classified as likely pathogenic, must be classified as pathogenic variant. We found this variant in two unrelated patients with familial ovarian and breast cancers.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000257990 SCV000591581 likely pathogenic Hereditary breast and ovarian cancer syndrome 2015-02-20 criteria provided, single submitter clinical testing
Invitae RCV000257990 SCV000636010 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-01-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 1706 of the BRCA1 protein (p.Gly1706Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been identified in individuals affected with hereditary breast and/or ovarian cancer (PMID: 25948282, 22144684, 17262179). This variant is also known as G602R in the literature (PMID: 25948282). ClinVar contains an entry for this variant (Variation ID: 267221). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Gly1706Glu) has been determined to be pathogenic (PMID: 15689452, 23867111, 27272900, 15923272, 17308087, 11979449, 17924331). This suggests that the glycine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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