ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3403C>G (p.Gln1135Glu) (rs80357136)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226768 SCV000289779 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-06-18 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 1135 of the BRCA1 protein (p.Gln1135Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs80357136, ExAC 0.01%). This variant has been observed in individuals with breast or ovarian cancer (PMID: 28692638, Invitae). However, in one individual pathogenic allele[s] were also identified in BRCA1, which suggests that this c.3403C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 240792). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 2016-08-19 criteria provided, single submitter clinical testing Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000764119 SCV000895092 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; FANCONI ANEMIA, COMPLEMENTATION GROUP S 2018-10-31 criteria provided, single submitter clinical testing

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