ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3652A>G (p.Ser1218Gly)

gnomAD frequency: 0.00001  dbSNP: rs80356894
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166540 SCV000217341 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-24 criteria provided, single submitter clinical testing The p.S1218G variant (also known as c.3652A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3652. The serine at codon 1218 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587400 SCV000699053 uncertain significance not specified 2019-03-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3652A>G (p.Ser1218Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246056 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3652A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000686085 SCV000813588 uncertain significance Hereditary breast ovarian cancer syndrome 2023-08-18 criteria provided, single submitter clinical testing 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 37536). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (rs80356894, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1218 of the BRCA1 protein (p.Ser1218Gly).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002477032 SCV002774469 uncertain significance not provided 2022-07-11 criteria provided, single submitter clinical testing The variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000008 (2/251300 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BRCA1 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington RCV000166540 SCV003846364 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Preventiongenetics, part of Exact Sciences RCV003407377 SCV004108707 uncertain significance BRCA1-related condition 2023-06-14 criteria provided, single submitter clinical testing The BRCA1 c.3652A>G variant is predicted to result in the amino acid substitution p.Ser1218Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41243896-T-C) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/37536/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Sharing Clinical Reports Project (SCRP) RCV000031117 SCV000053715 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2009-07-20 no assertion criteria provided clinical testing

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