11-108256240-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000051.4(ATM):c.2150G>C(p.Arg717Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000934 in 1,606,852 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.2150G>C | p.Arg717Pro | missense_variant | Exon 14 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151904Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250664Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135502
GnomAD4 exome AF: 0.00000894 AC: 13AN: 1454948Hom.: 0 Cov.: 30 AF XY: 0.00000691 AC XY: 5AN XY: 723866
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151904Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74178
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
The p.R717P variant (also known as c.2150G>C), located in coding exon 13 of the ATM gene, results from a G to C substitution at nucleotide position 2150. The arginine at codon 717 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
This missense variant replaces arginine with proline at codon 717 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has been identified in 4/281976 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. -
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Ataxia-telangiectasia syndrome Uncertain:2
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This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 717 of the ATM protein (p.Arg717Pro). This variant is present in population databases (rs768874297, gnomAD 0.04%). 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: 420303). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 36029002). 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. -
not specified Uncertain:1
Variant summary: ATM c.2150G>C (p.Arg717Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 0.00001 in 276434 control chromsomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (1.4e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.2150G>C, has been reported in the literature in an individual diagnosed with a carcinoma (specific location was not indicated in publication from Ritterhouse_2016). This report does not provide an unequivocal conclusion about association of the variant with Ataxia-Telangiectasia. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance. -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1
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not provided Uncertain:1
This variant is denoted ATM c.2150G>C at the cDNA level, p.Arg717Pro (R717P) at the protein level, and results in the change of an Arginine to a Proline (CGG>CCG). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in an extrauterine Mullerian carcinoma (Ritterhouse 2016). ATM Arg717Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg717Pro occurs at a position that is not conserved and is not located in a known functional domain (Stracker 2013, Tavtigian 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Arg717Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
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