Submissions for variant NM_000051.4(ATM):c.7559T>G (p.Met2520Arg)

gnomAD frequency: 0.00001  dbSNP: rs587782692

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132126	SCV000187194	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-29	criteria provided, single submitter	clinical testing	The c.7559T>G variant (also known as p.M2520R), located in coding exon 50 of the ATM gene, results from a T to G substitution at nucleotide position 7559. The methionine at codon 2520 is replaced by arginine, an amino acid with similar properties. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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.
GeneDx	RCV000522314	SCV000617132	likely pathogenic	not provided	2023-02-24	criteria provided, single submitter	clinical testing	Exonic splice variant demonstrated to cause aberrant splicing, resulting in a null allele in the majority of transcripts in a gene for which loss-of-function is a known mechanism of disease (External communication with Ambry Genetics and Invitae); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant has a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23532176)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627852	SCV000748736	pathogenic	Ataxia-telangiectasia syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2520 of the ATM protein (p.Met2520Arg). 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 (rs587782692, gnomAD 0.0009%). 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: 142749). 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. 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	RCV000132126	SCV002053664	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-28	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with arginine at codon 2520 of the ATM protein. Splice site prediction tools suggest that this variant may impact RNA splicing by creating a new splice acceptor site at position c.7560. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (communication with an external laboratories; ClinVar SCV000187194.7, SCV000748736.6). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251280 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.
Myriad Genetics, Inc.	RCV004589632	SCV005082077	likely pathogenic	Familial cancer of breast	2024-06-05	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].