ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5242G>T (p.Gly1748Cys) (rs397507245)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473758 SCV000549323 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 1748 of the BRCA1 protein (p.Gly1748Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. 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: 37650). 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.
GeneDx RCV000487391 SCV000566826 uncertain significance not provided 2015-06-08 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5242G>T at the cDNA level, p.Gly1748Cys (G1748C) at the protein level, and results in the change of a Glycine to a Cysteine (GGT>TGT). Using alternate nomenclature, this variant would be defined as BRCA1 5361G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gly1748Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gly1748Cys occurs at a position that is conserved across species and is located within a region containing the BRCT domains (Narod 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Gly1748Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000509724 SCV000608118 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Sharing Clinical Reports Project (SCRP) RCV000031231 SCV000053831 uncertain significance Breast-ovarian cancer, familial 1 2011-09-15 no assertion criteria provided clinical testing

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