ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4073A>G (p.Glu1358Gly) (rs397507225)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000031143 SCV000488071 uncertain significance Breast-ovarian cancer, familial 1 2015-12-23 criteria provided, single submitter clinical testing
GeneDx RCV000766672 SCV000570614 uncertain significance not provided 2016-06-08 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4073A>G at the cDNA level, p.Glu1358Gly (E1358G) at the protein level, and results in the change of a Glutamic Acid to a Glycine (GAG>GGG). Using alternate nomenclature, this variant would be defined as BRCA1 4192A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu1358Gly 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 Glu1358Gly occurs at a position that is not conserved and is located in the SCD domain and within the BRCA2, ATM, CHK2 and CDK2 binding domains (Chen 1998, Narod 2004, Clark 2012). 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 Glu1358Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Molecular Medicine,Queen's University RCV000481308 SCV000588054 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Color RCV000584349 SCV000688463 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Invitae RCV000637566 SCV000759030 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 1358 of the BRCA1 protein (p.Glu1358Gly). 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 (rs397507225, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 37562). 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.
Integrated Genetics/Laboratory Corporation of America RCV000481308 SCV000916813 uncertain significance not specified 2018-10-22 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4073A>G (p.Glu1358Gly) 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 4.1e-06 in 245614 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.4073A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031143 SCV000053743 uncertain significance Breast-ovarian cancer, familial 1 2007-09-24 no assertion criteria provided clinical testing

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