NM_000051.4:c.6145T>G
Variant summary
Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000051.4(ATM):c.6145T>G(p.Tyr2049Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2049C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | MANE Select | c.6145T>G | p.Tyr2049Asp | missense | Exon 42 of 63 | NP_000042.3 | ||
| ATM | NM_001351834.2 | c.6145T>G | p.Tyr2049Asp | missense | Exon 43 of 64 | NP_001338763.1 | |||
| C11orf65 | NM_001330368.2 | c.641-6989A>C | intron | N/A | NP_001317297.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | MANE Select | c.6145T>G | p.Tyr2049Asp | missense | Exon 42 of 63 | ENSP00000501606.1 | ||
| ATM | ENST00000452508.7 | TSL:1 | c.6145T>G | p.Tyr2049Asp | missense | Exon 43 of 64 | ENSP00000388058.2 | ||
| ATM | ENST00000527805.6 | TSL:1 | n.*1209T>G | non_coding_transcript_exon | Exon 40 of 61 | ENSP00000435747.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2Uncertain:1
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Variant summary: ATM c.6145T>G (p.Tyr2049Asp) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251404 control chromosomes. c.6145T>G has been reported in the literature in at-least four individuals affected with Ataxia-Telangiectasia as well as a VUS in settings of multigene panel testing among individuals with a variety of cancers (example, Podralska_2014, Maciejczyk_2019, Seligson_2019, Moens_2014, Pearlman_2021, Elitzur_2024). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31611883, 25502423, 34250417, 25614872, 30541756, 38917355). ClinVar contains an entry for this variant (Variation ID: 187481). Based on the evidence outlined above, the variant was classified as likely pathogenic.
This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2049 of the ATM protein (p.Tyr2049Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 25614872, 31611883). ClinVar contains an entry for this variant (Variation ID: 187481). Invitae Evidence 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 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Familial cancer of breast Pathogenic:2
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 38917355, 37438524, 31611883, 25614872].
Hereditary cancer-predisposing syndrome Pathogenic:2
This missense variant replaces tyrosine with aspartic acid at codon 2049 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in the compound heterozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 25614872, 31611883), indicating that this variant contributes to disease. 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.
The p.Y2049D variant (also known as c.6145T>G), located in coding exon 41 of the ATM gene, results from a T to G substitution at nucleotide position 6145. The tyrosine at codon 2049 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant has been identified in individuals diagnosed with ataxia telangiectasia (Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11; Maciejczyk M et al. Front Immunol, 2019 Sep;10:2322). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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.
Hereditary breast ovarian cancer syndrome Pathogenic:1
. According to the ACMG standard criteria we chose these criteria: PM2 (supporting pathogenic): Absent from controls , PM3 (strong pathogenic): found in trans in AT-patients: Maciejczyk et al und Podralska et al., PP3 (supporting pathogenic): REVEL: 0,83
not provided Uncertain:1
This variant is denoted ATM c.6145T>G at the cDNA level, p.Tyr2049Asp (Y2049D) at the protein level,and results in the change of a Tyrosine to an Aspartic Acid (TAT>GAT). This variant was observed in the compoundheterozygous state with another ATM variant in a pediatric patient with ataxia-telangiectasia (Podralska 2014). ATMTyr2049Asp was not observed in large population cohorts (Lek 2016). Since Tyrosine and Aspartic Acid differ inpolarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATMTyr2049Asp occurs at a position that is conserved across species and is located within the FAT domain (Stracker2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based oncurrently available information, it is unclear whether ATM Tyr2049Asp is pathogenic or benign. We consider it to be avariant of uncertain significance
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at