Submissions for variant NM_000051.4(ATM):c.2455T>C (p.Cys819Arg)

dbSNP: rs775644968

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000211457	SCV000268515	likely pathogenic	Ataxia-telangiectasia syndrome	2016-02-19	criteria provided, single submitter	clinical testing	This inherited recessive likely pathogenic mutation in the ATM gene was observed in combination with a second recessive pathogenic mutation in the ATM gene, NM_000051.2:c.8264_8268del, in a patient with ataxia-telangectasia.
Ambry Genetics	RCV000566647	SCV000672641	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-07	criteria provided, single submitter	clinical testing	The p.C819R variant (also known as c.2455T>C), located in coding exon 15 of the ATM gene, results from a T to C substitution at nucleotide position 2455. The cysteine at codon 819 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been confirmed in trans with a ATM pathogenic variant in an individual diagnosed with ataxia telangiectasia (Blanchard-Rohner G et al. Front Immunol, 2022 Jan;13:791522). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000211457	SCV001212903	uncertain significance	Ataxia-telangiectasia syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 819 of the ATM protein (p.Cys819Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 35154108). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 226114). 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 disruptive. 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.