rs876658572
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.1660delA(p.Thr554ArgfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T554T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 frameshift
Scores
Clinical Significance
Conservation
Publications
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
- ataxia telangiectasiaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- familial ovarian cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- gastric carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.1660delA | p.Thr554ArgfsTer2 | frameshift_variant | Exon 11 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461586Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727098 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2
This sequence change creates a premature translational stop signal (p.Thr554Argfs*2) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer, and an individual affected with ataxia-telangiectasia (PMID: 10677309, 17393301, 19781682, 22213089, 30197789). ClinVar contains an entry for this variant (Variation ID: 230448). For these reasons, this variant has been classified as Pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
The c.1660delA pathogenic mutation, located in coding exon 10 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 1660, causing a translational frameshift with a predicted alternate stop codon (p.T554Rfs*2). This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46). This variant has been identified in the homozygous state and/or in conjunction with other ATM variant(s) in individual(s) with features consistent with ataxia telangiectasia (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). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
This variant deletes 1 nucleotide in exon 11 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 been reported in individuals affected with breast cancer (PMID: 10677309, 17393301, 19781682). This variant has also been observed in the compound heterozygous state in an individual affected with autosomal recessive ataxia-telangiectasia (PMID: 22213089), indicating that this variant contributes to disease. 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 Pathogenic. -
Familial cancer of breast Pathogenic:2
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at