11-108316094-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000051.4(ATM):c.6179G>C(p.Arg2060Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.6179G>C | p.Arg2060Pro | missense_variant | Exon 42 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152082Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251258Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135780
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461780Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727194
GnomAD4 genome AF: 0.0000395 AC: 6AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74294
ClinVar
Submissions by phenotype
not provided Uncertain:3
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Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23532176) -
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Ataxia-telangiectasia syndrome Uncertain:2
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2060 of the ATM protein (p.Arg2060Pro). This variant is present in population databases (rs376521407, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 230875). 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) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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. -
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Hereditary cancer-predisposing syndrome Uncertain:2
This missense variant replaces arginine with proline at codon 2060 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. A different variant resulting in the same protein change, c.6179G>A (p.Arg2060His), has been detected with CHEK2 p.Ile157Thr in an individual suspected for hereditary breast and/or ovarian cancer and/or Lynch syndrome (PMID: 38136308). This variant has been identified in 3/282654 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. -
The p.R2060P variant (also known as c.6179G>C), located in coding exon 41 of the ATM gene, results from a G to C substitution at nucleotide position 6179. The arginine at codon 2060 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not specified Uncertain:1
Variant summary: The ATM c.6179G>C (p.Arg2060Pro) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 3/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 4/276988 control chromosomes (gnomAD) at a frequency of 0.0000144, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Other missense changes this residue (Arg2060Leu, Arg2060His and Arg2060Cys) have been classified as uncertain significance by clinical laboratories in ClinVar. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Familial cancer of breast Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at