rs876658711
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000051.4(ATM):c.4468A>G(p.Ser1490Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,434 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1490N) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4468A>G | p.Ser1490Gly | missense_variant | 30/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.4468A>G | p.Ser1490Gly | missense_variant | 30/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151700Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251292Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135802
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461734Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727166
GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151700Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74058
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1490 of the ATM protein (p.Ser1490Gly). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with renal clear cell carcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 230691). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2023 | The p.S1490G variant (also known as c.4468A>G), located in coding exon 29 of the ATM gene, results from an A to G substitution at nucleotide position 4468. The serine at codon 1490 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in a renal clear cell carcinoma patient from a cohort of 4034 cancer cases from The Cancer Genome Atlas (Lu C et al. Nat Commun, 2015 Dec;6:10086). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 13, 2023 | This missense variant replaces serine with glycine at codon 1490 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with renal clear cell carcinoma (PMID: 26689913). This variant has been identified in 2/251292 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 14, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with renal carcinoma (Lu et al.. 2015); This variant is associated with the following publications: (PMID: 29684080, 26689913) - |
ATM-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 01, 2023 | The ATM c.4468A>G variant is predicted to result in the amino acid substitution p.Ser1490Gly. This variant has been reported in an individual with kidney renal clear cell carcinoma (Table S12, Lu et al. 2015. PubMed ID: 26689913). This variant is reported in 2 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/11-108163377-A-G). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/230691/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at