Submissions for variant NM_000051.4(ATM):c.1695A>G (p.Glu565=)

gnomAD frequency: 0.00001  dbSNP: rs780932013

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472970	SCV000547136	pathogenic	Ataxia-telangiectasia syndrome	2023-08-16	criteria provided, single submitter	clinical testing	This sequence change affects codon 565 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs780932013, 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: 407723). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (Invitae; external communication). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000483767	SCV000567907	likely pathogenic	not provided	2023-11-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000563909	SCV000660618	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-12-15	criteria provided, single submitter	clinical testing	The c.1695A>G variant (also known as p.E565E), located in coding exon 10 of the ATM gene, results from an A to G substitution at nucleotide position 1695. This nucleotide substitution does not change the at codon 565. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000563909	SCV000681992	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-03	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the 1695 position of the ATM gene. 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 SCV000660618.4). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282680 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779760	SCV000916536	uncertain significance	not specified	2024-06-27	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1695A>G alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: four predict the variant strengthens a cryptic 5' donor site. However, these predictions have yet to be confirmed by published functional studies. The variant allele was found at a frequency of 8e-06 in 251276 control chromosomes (gnomAD v2.1), including two carriers who were above age 75 year and were also part of the non-cancer datasets (gnomAD v2.1 and v3.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1695A>G in individuals affected with Ataxia-Telangiectasia (or other ATM-related phenotypes) and no experimental evidence demonstrating its impact on mRNA have been reported. ClinVar contains an entry for this variant (Variation ID: 407723), and one of the ClinVar submitters reported abnormal splicing in the set of samples tested (Ambry internal data), however these results were not available for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000563909	SCV002531064	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-30	criteria provided, single submitter	curation
Baylor Genetics	RCV003470443	SCV004206869	likely pathogenic	Familial cancer of breast	2023-10-22	criteria provided, single submitter	clinical testing