Submissions for variant NM_000059.4(BRCA2):c.3154G>A (p.Ala1052Thr)

dbSNP: rs730881520

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589646	SCV000210306	uncertain significance	not provided	2014-09-10	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.3154G>A at the cDNA level, p.Ala1052Thr (A1052T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala1052Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala1052Thr occurs at a position that is poorly conserved across species and accepts Threonine in several species. This variant is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ala1052Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000567319	SCV000668808	uncertain significance	Hereditary cancer-predisposing syndrome	2018-06-29	criteria provided, single submitter	clinical testing	The p.A1052T variant (also known as c.3154G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 3154. The alanine at codon 1052 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589646	SCV000694669	uncertain significance	not provided	2016-07-31	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.3154G>A (p.Ala1052Thr) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured here due to low reliability) predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP), nor has it been to our knowledge, reported in affected individuals via publications. An internal LCA specimen reports the variant to co-occur with a pathogenic BRCA1 variant, c.4484G>T (p.Arg1485Met - classified as pathogenic by LCA). A reputable clinical laboratory cites the variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information.
Color Diagnostics, LLC DBA Color Health	RCV000567319	SCV000903460	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1052 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516426	SCV002939597	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1052 of the BRCA2 protein (p.Ala1052Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182195). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000567319	SCV003851725	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).