11-108347318-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000051.4(ATM):c.8624A>G(p.Asn2875Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,518 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 (★★).
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.8624A>G | p.Asn2875Ser | missense_variant | Exon 59 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250406Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135378
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459518Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726214
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:2
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This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 2875 of the ATM protein (p.Asn2875Ser). This variant is present in population databases (rs587782451, gnomAD 0.0009%). This missense change has been observed in individual(s) with ataxia telangiectasia, colorectal cancer, and/or familial breast cancer (PMID: 19440741, 30303537, 30730459). ClinVar contains an entry for this variant (Variation ID: 142418). 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. -
Hereditary cancer-predisposing syndrome Uncertain:2
The p.N2875S variant (also known as c.8624A>G), located in coding exon 58 of the ATM gene, results from an A to G substitution at nucleotide position 8624. The asparagine at codon 2875 is replaced by serine, an amino acid with highly similar properties. This variant was reported in a compound heterozygous state with a frameshift mutation in a patient diagnosed with ataxia telangiectasia, however, phase was not determined (Anheim, M. Neurogenetics. 2010 Feb;11(1):1-12). This alteration has been identified in cohorts of breast and colon cancer patients (Tavtigian SV et al. Am J Hum Genet. 2009 Oct;85:427-46; Girard E et al. Int J Cancer. 2019 04;144:1962-1974; You YN et al. Dis Colon Rectum. 2019 04;62:429-437). Based on internal structural analysis, this alteration eliminates a residue that is critical for binding of the MgATP substrate and therefore impairs its catalytic activity (Gerlits O et al. J. Biol. Chem., 2015 Jun;290:15538-48). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analyses. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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not provided Uncertain:1
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast and colon cancers (Girard 2019, You 2019); Observed with a nonsense variant in an individual with ataxia telangiectasia, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Anheim 2010); This variant is associated with the following publications: (PMID: 27304073, 30730459, 30303537, 19440741, 25232094) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at