ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3113A>C (p.Glu1038Ala) (rs16941)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233884 SCV000289771 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-02-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 1038 of the BRCA1 protein (p.Glu1038Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000562497 SCV000673029 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-01 criteria provided, single submitter clinical testing The p.E1038A variant (also known as c.3113A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 3113. The glutamic acid at codon 1038 is replaced by alanine, an amino acid with dissimilar 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.
Color Health, Inc RCV000562497 SCV001355184 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000500860 SCV001363878 uncertain significance not specified 2019-02-19 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3113A>C (p.Glu1038Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276670 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.3113A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Another variant at this position, c.3113A>G causing a different amino acid change, p.Glu1038Gly, has been reported countless times and classified as benign. Two 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353949 SCV000591426 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Glu1038Ala variant has not been identified previously. Another variant impacting the same amino acid (c.3113A>G, p.Glu1038Gly) is a common polymorphism with no clinical significance (Abkevich 2004, Pilato 2010, Balraj 2002, Borg 2010, Diez 2003, and others). The p.Glu1038 residue is not conserved in mammals, and in silico predictions provide inconsistent findings for both p.Glu1038Gly and p.Glu1038Ala variants and this information is not very predictive of pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. This variant is classified as Predicted Benign.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735473 SCV000863610 likely benign Breast and/or ovarian cancer 2013-03-25 no assertion criteria provided clinical testing

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