ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1724A>G (p.Glu575Gly) (rs111539978)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165640 SCV000216376 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000234745 SCV000289750 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 575 of the BRCA1 protein (p.Glu575Gly). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs111539978, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 186110). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000587405 SCV000293153 uncertain significance not provided 2016-09-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1724A>G at the cDNA level, p.Glu575Gly (E575G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAA>GGA). Using alternate nomenclature, this variant would be defined as BRCA1 1843A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu575Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu575Gly occurs at a position that is not conserved and is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Glu575Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235825 SCV000600265 uncertain significance not specified 2017-07-19 criteria provided, single submitter clinical testing
Color RCV000165640 SCV000682979 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587405 SCV000698884 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.1724A>G (p.Glu575Gly) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). It is located outside of currently known functional domains (Ring finger, S-R, and BCRT). This variant was found in 1/121130 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It has been reported in literature in a validation study of high resolution melting without evidence for or against pathogenicity (Hondow_2011). It has also been reported by UMD in two samples without co-occurrence with other deleterious variants in BRCA1/2. Multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Another missense variant at the same codon, Glu575Lys, is reported in UMD five times, once with co-occurrence with a deleterious variant BRCA1 c.5030_5033delCTAA and the is classified as uncertain significance. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.

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