chr11-108332848-TG-GC
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1PM1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.7875_7876delTGinsGC(p.AspAla2625GluPro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.7875_7876delTGinsGC | p.AspAla2625GluPro | missense_variant | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:5Other:1
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Variant summary: ATM c.7875_7876delinsGC (p.Asp2625_Ala2626delinsGluPro) results in an in-frame deletion-insertion that is predicted to delete two amino acids and insert to amino acids from the encoded protein. The variant was absent in 250852 control chromosomes (gnomAD). c.7875_7876delinsGC has been reported in the literature in multiple bi-allelic individuals affected with Ataxia-Telangiectasia (example: Verhagen_2012). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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This variant, c.7875_7876delinsGC, is a complex sequence change that results in the substitution of 2 amino acid(s) in the ATM protein (p.Asp2625_Ala2626delinsGluPro). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with ataxia telangiectasia (PMID: 9521587, 10980530, 19535770, 22213089). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as a double missense variant, D2625E and A2626P on the same chromosome. ClinVar contains an entry for this variant (Variation ID: 3030). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects ATM function (PMID: 22213089). For these reasons, this variant has been classified as Pathogenic. -
Familial cancer of breast Pathogenic:5
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ACMG criteria used to clasify this variant: PS4, PS3_MOD, PM3, PM2_SUP, PP3 -
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This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9521587, 10980530, 19535770]. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.7875_7876delTGinsGC variant (also known as p.D2625_A2626delinsEP), located in coding exon 52 of the ATM gene, results from the deletion of TG and the insertion of GC at nucleotide positions 7875 and 7876. This causes amino acid substitutions at two highly-conserved codons: the aspartic acid at codon 2625 is replaced by glutamic acid and the alanine at codon 2626 is replaced by proline. This alteration has been reported in multiple ataxia-telangiectasia (AT) families, both homozygous and in trans with known pathogenic mutations (van Belzen MJ et al. Hum. Genet. 1998 Feb;102(2):187-91; Li A and Swift M. Am. J. Med. Genet. 2000 May;92(3):170-7; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun; 70(2):122-33; Laake K et al. Hum. Mutat. 2000 Sep;16(3):232-46; Dörk T et al. Am. J. Med. Genet. A 2004 Apr;126A(3):272-7; Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71; Driessen GJ et al. J. Allergy Clin. Immunol. 2013 May;131(5):1367-75.e9). In one study, this variant was associated with complete absence of ATM protein in one homozygous AT patient (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70(2):122-33), while a second study detected ATM protein, but no ATM kinase activity in four homozygous AT patients (Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
This missense variant replaces aspartic acid and alanine at codons 2625 and 2626 of the ATM protein with glutamic acid and proline. This variant has been reported in the homozygous state or compound heterozygous state with another pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 9521587, 10873394, 11104561, 15054841, 17985259, 19535770, 21778326, 22213089, 25037873, 25122203, 30549301, 31050087). Cells derived from some of these individuals have shown reduced ATM kinase activity (PMID: 22213089, 30549301, 31050087). In a large international case-control study, this variant was reported in 8/60466 breast cancer cases and 7/53461 controls (PMID: 33471991). This variant has also been reported in an individual affected with pancreatic cancer (PMID: 29922827). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
not provided Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at