Submissions for variant NM_000051.4(ATM):c.5236G>A (p.Gly1746Arg)

dbSNP: rs1060501571

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV003985355	SCV004565388	pathogenic	Familial cancer of breast	2024-01-25	reviewed by expert panel	curation	The c.5236G>A (p.Gly1746Arg) 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. This variant was observed in an individual with Ataxia-Telangiectasia (PMID:26896183), and is absent from gnomAD v2.1.1. 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), PM2_Supporting, PM3_Supporting, PM5_Supporting).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465365	SCV000546760	uncertain significance	Ataxia-telangiectasia syndrome	2022-09-15	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 407510). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia (PMID: 26896183). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1746 of the ATM protein (p.Gly1746Arg). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Ambry Genetics	RCV000566161	SCV000667843	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-27	criteria provided, single submitter	clinical testing	The c.5236G>A variant (also known as p.G1746R), located in coding exon 34 of the ATM gene, results from a G to A substitution at nucleotide position 5236. The glycine at codon 1746 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in 1 individual from the UK diagnosed with ataxia-telangiectasia (Jackson TJ et al. Dev Med Child Neurol, 2016 07;58:690-7). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor and native splice donor sites. 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.