Submissions for variant NM_007294.4(BRCA1):c.3403C>G (p.Gln1135Glu)

dbSNP: rs80357136

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000226768	SCV000289779	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-03-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1135 of the BRCA1 protein (p.Gln1135Glu). This variant is present in population databases (rs80357136, gnomAD 0.006%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 28692638; Invitae). ClinVar contains an entry for this variant (Variation ID: 240792). 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.
GeneDx	RCV000484753	SCV000573057	uncertain significance	not provided	2017-02-01	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.3403C>G at the cDNA level, p.Gln1135Glu (Q1135E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). Using alternate nomenclature, this variant would be defined as BRCA1 3522C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gln1135Glu 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 Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Gln1135Glu occurs at a position that is not conserved and is not located in a known functional domain. 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 Gln1135Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000568567	SCV000673039	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-16	criteria provided, single submitter	clinical testing	The p.Q1135E variant (also known as c.3403C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 3403. The glutamine at codon 1135 is replaced by glutamic acid, an amino acid with highly similar properties. This variant was identified in 1/826 unselected Chinese ovarian cancer patients (Wu X et al. Int J Gynecol Cancer, 2017 10;27:1650-1657). 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.
Fulgent Genetics, Fulgent Genetics	RCV000764119	SCV000895092	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S	2018-10-31	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000568567	SCV003850446	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).