Submissions for variant NM_000051.4(ATM):c.7307G>A (p.Arg2436Lys)

dbSNP: rs786203394

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166679	SCV000217487	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-07	criteria provided, single submitter	clinical testing	The c.7307G>A variant (also known as p.R2436K), located in coding exon 48 of the ATM gene, results from a G to A substitution at nucleotide position 7307. The amino acid change results in arginine to lysine at codon 2436, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 48, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Internal RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same donor site, c.7307+1G>A, has been shown to have a similar impact on splicing and has been reported in an individual diagnosed with ataxia-telangiectasia (AT) (Birrell GW et al. Hum. Mutat., 2005 Jun;25:593). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230377	SCV000283045	pathogenic	Ataxia-telangiectasia syndrome	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2436 of the ATM protein (p.Arg2436Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs786203394, gnomAD 0.003%). This missense change has been observed in individuals with ataxia-telangiectasia (PMID: 35260754). ClinVar contains an entry for this variant (Variation ID: 187003). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000166679	SCV001339681	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the last nucleotide of exon 49 of the ATM gene and replaces arginine with lysine at codon 2436 of the ATM protein. Splice site prediction tools suggest that this variant may impact RNA splicing. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000217487.6). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported in a cohort of individuals affected with ataxia-telangiectasia (PMID: 35260754). This variant has been identified in 1/248522 chromosomes 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV003338435	SCV004047577	uncertain significance	Familial cancer of breast		criteria provided, single submitter	clinical testing	The missense variant c.7307G>A(p.Arg2436Lys) in ATM gene has been submitted to ClinVar as a Variant of Uncertain Significance and Likely Pathogenic with a phenotype of ataxia telangiectasia, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Arg2436Lys variant has allele frequency 0.0004% in gnomAD exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Arg at position 2436 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. The missense variant is present at the splice site and nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (Buratti et al.).For these reasons, this variant has been classified as Uncertain Significance (VUS).
Baylor Genetics	RCV003338435	SCV005057166	likely pathogenic	Familial cancer of breast	2023-12-06	criteria provided, single submitter	clinical testing
GeneDx	RCV004724961	SCV005331582	likely pathogenic	not provided	2024-03-13	criteria provided, single submitter	clinical testing	Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23532176, 35729272, 35260754)
Natera, Inc.	RCV000230377	SCV001458465	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739538	SCV005362685	likely pathogenic	ATM-related disorder	2024-09-17	no assertion criteria provided	clinical testing	The ATM c.7307G>A variant is predicted to result in the amino acid substitution p.Arg2436Lys. This variant has been reported in the literature in two individuals with Ataxia Telangiectasia (Rawat et al. 2022. PubMed ID: 35260754). In addition, external RNA studies suggest this variant causes altered splicing and would result in a disrupted protein product (https://www.ncbi.nlm.nih.gov/clinvar/variation/187003/). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations in ClinVar ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/187003/). Based on the available evidence this variant is interpreted as likely pathogenic.