Submissions for variant NM_000051.4(ATM):c.172G>T (p.Asp58Tyr)

dbSNP: rs876660661

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222411	SCV000278275	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-10	criteria provided, single submitter	clinical testing	The c.172G>T variant (also known as p.D58Y), located in coding exon 2 of the ATM gene, results from a G to T substitution at nucleotide position 172. The aspartic acid at codon 58 is replaced by tyrosine, an amino acid with highly dissimilar properties. This nucleotide position is highly conserved in available vertebrate species. 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). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627984	SCV000748871	pathogenic	Ataxia-telangiectasia syndrome	2024-04-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 58 of the ATM protein (p.Asp58Tyr). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35806449). ClinVar contains an entry for this variant (Variation ID: 233820). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 35806449; 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	RCV000222411	SCV001733842	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-09	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 58 of the ATM protein. 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 to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar SCV000278275.6). In addition, RNAseq studies showed abnormal splicing that resulted in a premature stop codon as well as some full-length transcript (PMID: 35806449). This variant has been reported in an individual affected with breast cancer (PMID: 35806449). This variant has not been identified 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.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV002265695	SCV002548544	uncertain significance	Familial cancer of breast	2022-05-15	criteria provided, single submitter	clinical testing	ATM:c.172G>T variant is absent from the large population studies (GnomAd). The variant is predicted to create a de novo donor splice site in exon 3 by in silico splicing tools. Functional RNA study has shown that the variant causes an incomplete splicing aberration that causes the creation of a premature stop codon (PMID: 35806449). Additionally, the variant also produced a slightly expressed full-length transcript. Therefore the variant was classified as variant of uncertain significance (ACMG/AMP: PM2-supp, PP3, PS3-m)