ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.922A>G (p.Ser308Gly) (rs55767801)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766450 SCV000567142 uncertain significance not provided 2015-07-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.922A>G at the cDNA level, p.Ser308Gly (S308G) at the protein level, and results in the change of a Serine to a Glycine (AGC>GGC). Using alternate nomenclature, this variant would be defined as BRCA1 1041A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ser308Gly 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 Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser308Gly occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located in in a SWI/SNF binding domain (Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Ser308Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481247 SCV000600446 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing
Color RCV000580929 SCV000683377 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-22 criteria provided, single submitter clinical testing
Invitae RCV000637630 SCV000759097 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-22 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 308 of the BRCA1 protein (p.Ser308Gly). 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 BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 419382). 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: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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