rs1555152058
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2_SupportingPM4PM3
This summary comes from the ClinGen Evidence Repository: The c.9145_9146del variant in ATM is predicted to cause a change in the length of the protein (p.Phe3049Profs*13) due to a frameshift of 8 amino acids and an extension of an additional 4 amino acids. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID:10817650). This variant is absent from gnomAD v4.1.0. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM4, PM3, PM2_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA658797748/MONDO:0700270/020
Frequency
Consequence
NM_000051.4 frameshift
Scores
Clinical Significance
Conservation
Publications
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.9145_9146delTT | p.Phe3049ProfsTer13 | frameshift_variant | Exon 63 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:2
- -
This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10817650, 16266405, 25614872, 15039971, 21965147]. -
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
This variant deletes 2 nucleotides in exon 63 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -
The c.9145_9146delTT variant, located in coding exon 62 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 9145 to 9146, causing a translational frameshift with a predicted alternate stop codon (p.F3049Pfs*13). This alteration has been reported in a compound heterozygous state in a cohort of families with ataxia telangiectasia (A-T) in the United States and Canada (Li A et al. Am. J. Med. Genet., 2000 May;92:170-7). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of ATM, is not expected to trigger nonsense-mediated mRNA decay, and results in the alteration of the last 8 amino acids and elongation of the protein by 4 amino acids. The exact functional impact of these altered/inserted amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Ataxia-telangiectasia syndrome Pathogenic:1
This sequence change results in a frameshift in the ATM gene (p.Phe3049Profs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8 amino acid(s) of the ATM protein and extend the protein by 4 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with ataxia-telangiectasia (PMID: 10817650). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 524412). This variant disrupts the FATC domain, which spans the last 33 amino acids of the ATM protein and is required for ATM kinase activity in response to DNA damage (PMID: 19781682, 16603769). While functional studies have not been performed to directly test the effect of this variant on ATM protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
ATM-related cancer predisposition Uncertain:1
The c.9145_9146del variant in ATM is predicted to cause a change in the length of the protein (p.Phe3049Profs*13) due to a frameshift of 8 amino acids and an extension of an additional 4 amino acids. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID: 10817650). This variant is absent from gnomAD v4.1.0. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM4, PM3, PM2_Supporting) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at