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

dbSNP: rs16941

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233884	SCV000289771	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-03-19	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 240786). This missense change has been observed in individual(s) with ovarian cancer (PMID: 28692638). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 1038 of the BRCA1 protein (p.Glu1038Ala).
Ambry Genetics	RCV000562497	SCV000673029	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-31	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 variant was identified in a cohort of 826 unselected Chinese ovarian cancer patients (Wu X et al. Int J Gynecol Cancer, 2017 Oct;27:1650-1657). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	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.
CeGaT Center for Human Genetics Tuebingen	RCV001726066	SCV001961694	uncertain significance	not provided	2021-08-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV003607273	SCV002579362	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP
University of Washington Department of Laboratory Medicine, University of Washington	RCV000562497	SCV003849126	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).
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