Submissions for variant NM_000051.4(ATM):c.5734G>C (p.Val1912Leu)

dbSNP: rs1064794105

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483178	SCV000567844	uncertain significance	not provided	2015-09-04	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.5734G>C at the cDNA level, p.Val1912Leu (V1912L) at the protein level, and results in the change of a Valine to a Leucine (GTT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Val1912Leu 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 Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. ATM Val1912Leu occurs at a position where amino acids with properties similar to Valine are tolerated across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Val1912Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001217633	SCV001389480	uncertain significance	Ataxia-telangiectasia syndrome	2022-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1912 of the ATM protein (p.Val1912Leu). 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 ATM protein function. ClinVar contains an entry for this variant (Variation ID: 419785). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV004023127	SCV005018433	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-20	criteria provided, single submitter	clinical testing	The p.V1912L variant (also known as c.5734G>C), located in coding exon 37 of the ATM gene, results from a G to C substitution at nucleotide position 5734. The valine at codon 1912 is replaced by leucine, an amino acid with highly similar properties. 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.