11-108333951-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000051.4(ATM):c.7993C>G(p.Pro2665Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,609,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. P2665L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.7993C>G | p.Pro2665Ala | missense_variant | Exon 54 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151734Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458246Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 725670
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151734Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74112
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2665 of the ATM protein (p.Pro2665Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 453714). 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 expected to disrupt ATM protein function with a positive 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 proline with alanine at codon 2665 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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. -
The p.P2665A variant (also known as c.7993C>G), located in coding exon 53 of the ATM gene, results from a C to G substitution at nucleotide position 7993. The proline at codon 2665 is replaced by alanine, an amino acid with highly similar 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at