ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2299A>G (p.Ser767Gly)

gnomAD frequency: 0.00003  dbSNP: rs80357194
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047788 SCV000075801 uncertain significance Hereditary breast ovarian cancer syndrome 2022-09-20 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 767 of the BRCA1 protein (p.Ser767Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 37461). 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. 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.
Ambry Genetics RCV000130067 SCV000184894 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-29 criteria provided, single submitter clinical testing The p.S767G variant (also known as c.2299A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 2299. The serine at codon 767 is replaced by glycine, an amino acid with similar properties. In one study, this alteration was detected in one patient with unilateral breast cancer and was predicted to be most likely neutral based on Align-GVGD in silico analyses (Borg A et al. Hum. Mutat. 2010; 31:E1200-40). This amino acid position is poorly conserved on species alignment. 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.
GeneDx RCV000485116 SCV000565778 uncertain significance not provided 2022-03-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2418 A>G; This variant is associated with the following publications: (PMID: 15343273, 20104584)
Color Diagnostics, LLC DBA Color Health RCV000130067 SCV000909348 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-16 criteria provided, single submitter clinical testing This missense variant replaces serine with glycine at codon 767 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 20104584, 33606809). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485116 SCV001133523 uncertain significance not provided 2023-08-14 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 33606809 (2021), 20104584 (2010)), and described to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000026 (4/152232 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. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics RCV000031042 SCV001140577 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV000031042 SCV002512512 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2021-10-21 criteria provided, single submitter clinical testing ACMG classification criteria: BP4 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003155044 SCV003844478 uncertain significance not specified 2023-02-09 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2299A>G (p.Ser767Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251084 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2299A>G has been reported in the literature in individuals affected with Breast Cancer (e.g. Borg_2010, Sandoval_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000130067 SCV003847773 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).
Sharing Clinical Reports Project (SCRP) RCV000031042 SCV000053636 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2008-03-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031042 SCV000144371 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-11-25 no assertion criteria provided clinical testing

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