Submissions for variant NM_000051.4(ATM):c.6807G>A (p.Gln2269=)

gnomAD frequency: 0.00001  dbSNP: rs587780638

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV003985275	SCV004565384	pathogenic	Familial cancer of breast	2024-01-25	reviewed by expert panel	curation	The c.6807G>A variant in ATM has been demonstrated to cause aberrant splicing, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (Ambry internal data). This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. The highest population minor allele frequency in gnomAD v3.1.2 is [0.009614%] (1/10402 alleles) in European (Finnish) population, which is lower than the ClinGen HBOP threshold for PM2_Supporting, meeting this criterion. This variant has been detected in at least 1 individual with Ataxia-Telangiectasia (PMID: 30549301). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PVS1(RNA), PM3_supporting, PM2_supporting, PM5_supporting).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122879	SCV000166137	pathogenic	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change affects codon 2269 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with breast cancer and/or clinical features of ataxia-telangiectasia (PMID: 30549301; Invitae). 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: 135775). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 46 and introduces a premature termination codon (PMID: 30549301; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000213885	SCV000278570	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	The c.6807G>A variant (also known as p.Q2269Q), located in coding exon 45 of the ATM gene, results from a G to A substitution at nucleotide position 6807. This nucleotide substitution does not change the glutamine at codon 2269. However, this change occurs in the last base pair of coding exon 45, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported in the literature an individual diagnosed with variant ataxia-telangiectasia (A-T) (Schon K et al. Ann. Neurol., 2019 02;85:170-180). In addition, this alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000213885	SCV001358591	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This synonymous variant substitutes the conserved G with A at the last nucleotide of exon 46 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies demonstrating abnormal splicing have been reported in ClinVar (ClinVar variation ID: 135775). This variant has been reported in trans with a pathogenic ATM truncation mutation in an individual affected with an attenuated form of ataxia telangiectasia (PMID: 30549301). The lymphoblastoid cell line derived from this individual has shown some normal ATM protein with residual kinase activity, which may be attributed to a leaky splice site mutation. This variant has also been reported in individuals affected with breast cancer (PMID: 28779002; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798398	SCV002042789	pathogenic	Breast and/or ovarian cancer	2024-03-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001288455	SCV002558416	likely pathogenic	not provided	2022-07-28	criteria provided, single submitter	clinical testing	Located at the last nucleotide of the exon and demonstrated to result in abnormal splicing (External communication with Ambry; ClinVar); Observed with a pathogenic ATM variant in patients with Ataxia-Telangiectasia in published literature but it is not known whether the variants occurred on the same (in cis) allele or on opposite (in trans) alleles (Jackson et al., 2016; Schon et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Identified in a patient with breast cancer in published literature (Decker et al., 2017); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 15928302, 28779002, 17576681, 26896183, 30549301)
Myriad Genetics, Inc.	RCV003985275	SCV004933565	likely pathogenic	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].
Athena Diagnostics	RCV001288455	SCV001475566	uncertain significance	not provided	2020-07-27	flagged submission	clinical testing