Submissions for variant NM_000051.4(ATM):c.5076A>C (p.Lys1692Asn)

gnomAD frequency: 0.00001  dbSNP: rs767841041

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235459	SCV000293954	uncertain significance	not provided	2016-02-11	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.5076A>C at the cDNA level, p.Lys1692Asn (K1692N) at the protein level, and results in the change of a Lysine to an Asparagine (AAA>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Lys1692Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Lys1692Asn occurs at a position that is not conserved 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 evidence, it is unclear whether ATM Lys1692Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000470161	SCV000546924	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1692 of the ATM protein (p.Lys1692Asn). This variant is present in population databases (rs767841041, gnomAD 0.002%). 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: 246410). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Ambry Genetics	RCV000575591	SCV000667862	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-18	criteria provided, single submitter	clinical testing	The p.K1692N variant (also known as c.5076A>C), located in coding exon 33 of the ATM gene, results from an A to C substitution at nucleotide position 5076. The lysine at codon 1692 is replaced by asparagine, an amino acid with similar 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 Diagnostics, LLC DBA Color Health	RCV000575591	SCV001343979	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567787	SCV005053018	uncertain significance	Familial cancer of breast	2023-11-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000470161	SCV002078451	uncertain significance	Ataxia-telangiectasia syndrome	2021-07-02	no assertion criteria provided	clinical testing