ClinVar Miner

Submissions for variant NM_007294.4(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 2018-06-29 criteria provided, single submitter clinical testing The p.E575G variant (also known as c.1724A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 1724. The glutamic acid at codon 575 is replaced by glycine, an amino acid with similar properties. This amino acid position is not 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.
Invitae RCV000234745 SCV000289750 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-02 criteria provided, single submitter clinical testing
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 RCV000587405 SCV000600265 uncertain significance not provided 2019-11-15 criteria provided, single submitter clinical testing
Color Health, Inc RCV000165640 SCV000682979 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420708 SCV000698884 likely benign not specified 2021-05-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1724A>G (p.Glu575Gly) 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 allele was found at a frequency of 3.6e-05 in 364166 control chromosomes, predominantly at a frequency of 0.00024 within the African or African-American subpopulation in the gnomAD database (v2.1 and v3.1 datasets). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (0.001). However, the variant was also reported from the southern part of Africa with an even higher allele frequency, i.e. 0.029 (6/208 alleles), including 1 homozygote (in the GenomeAsia 100K database). In addition, it was found in 1/ 2559 African American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). These data suggest that the variant could be a benign polymorphism. The variant. c.1724A>G has been reported in the literature in a validation study using high resolution melting for BRCA mutation scanning, but without evidence for or against pathogenicity (Hondow_2011). It has also been reported in the BRCA Share database (formerly UMD-BRCA1) in one proband (without co-occurrence with other deleterious variants in BRCA1/2). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

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