Submissions for variant NM_007294.4(BRCA1):c.4073A>G (p.Glu1358Gly)

gnomAD frequency: 0.00001  dbSNP: rs397507225

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000031143	SCV000488071	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 Diagnostics, LLC DBA Color Health	RCV000584349	SCV000688463	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-08	criteria provided, single submitter	clinical testing
Invitae	RCV000637566	SCV000759030	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-12-11	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 37562). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is present in population databases (rs397507225, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1358 of the BRCA1 protein (p.Glu1358Gly).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Ambry Genetics	RCV000584349	SCV001183470	uncertain significance	Hereditary cancer-predisposing syndrome	2018-10-25	criteria provided, single submitter	clinical testing	The p.E1358G variant (also known as c.4073A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 4073. The glutamic acid at codon 1358 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.
Mendelics	RCV000481308	SCV002517951	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000584349	SCV003851312	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)	RCV000031143	SCV000053743	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2007-09-24	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031143	SCV004244010	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing