ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2296A>G (p.Ser766Gly) (rs398122655)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457419 SCV000549423 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-18 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 766 of the BRCA1 protein (p.Ser766Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 91581). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on BRCA1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000585955 SCV000568127 uncertain significance not provided 2018-05-11 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2296A>G at the cDNA level, p.Ser766Gly (S766G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). Using alternate nomenclature, this variant would be defined as BRCA1 2415A>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA1 Ser766Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and a region known to interaction with multiple other proteins (Narod 2004, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Ser766Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482626 SCV000600281 uncertain significance not specified 2017-07-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000564749 SCV000661143 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000564749 SCV000683024 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000585955 SCV000698935 uncertain significance not provided 2017-04-20 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2296A>G (p.Ser766Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant is not located in any known domain (InterPro). The variant of interest is absent in a large, broad control population, ExAC, 0/121386 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Counsyl RCV000077098 SCV000785580 uncertain significance Breast-ovarian cancer, familial 1 2017-09-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077098 SCV000108895 uncertain significance Breast-ovarian cancer, familial 1 2009-05-12 no assertion criteria provided clinical testing

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