Submissions for variant NM_000051.4(ATM):c.3176C>T (p.Ala1059Val)

gnomAD frequency: 0.00001  dbSNP: rs761590782

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217486	SCV000275076	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-11	criteria provided, single submitter	clinical testing	The p.A1059V variant (also known as c.3176C>T), located in coding exon 21 of the ATM gene, results from a C to T substitution at nucleotide position 3176. The alanine at codon 1059 is replaced by valine, an amino acid with similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000217486	SCV000682108	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1059 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders 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	RCV000704863	SCV000833834	uncertain significance	Ataxia-telangiectasia syndrome	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1059 of the ATM protein (p.Ala1059Val). This variant is present in population databases (rs761590782, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 231281). 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 ATM 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237776	SCV002010832	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV003237776	SCV004023469	uncertain significance	not provided	2023-08-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with kidney cancer (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 29684080, 19781682)
Baylor Genetics	RCV003469026	SCV004210190	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing