11-108244873-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5_SupportingPVS1PM2_SupportingPM3
This summary comes from the ClinGen Evidence Repository: The c.748C>T (p.Arg250*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in numerous individuals with Ataxia-Telangiectasia (PMIDs: 10330348, 12552559, 20840352, 21778326, 22006793, 26896185, 30816533, 31611883). The highest population minor allele frequency in gnomAD v2.1.1 0.00003 (1/34560) which meets the PM2 threshold of n≤1 alleles when sub-population frequency is >0.00001 (PM2_Supporting met). In summary, this variant meets criteria to be classified as pathogenic 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. (PVS1, PM5_Supporting, PM3_VeryStrong, PM2_Supporting) LINK:https://erepo.genome.network/evrepo/ui/classification/CA336868/MONDO:0700270/020
Frequency
Consequence
NM_000051.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | c.748C>T | p.Arg250* | stop_gained | Exon 7 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251002Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135654
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461624Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727120
GnomAD4 genome
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:4
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This sequence change creates a premature translational stop signal (p.Arg250*) 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 present in population databases (rs772821016, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 10330348, 12552559, 22006793, 28724667). ClinVar contains an entry for this variant (Variation ID: 216024). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:4
This variant changes 1 nucleotide in exon 7 of the ATM gene, creating a premature translation stop signal. In addition, RNA extracted from carrier-derived lymphoblastoid cells have shown the skipping of exon 7 (also known as exon 9 in the literature; PMID: 10330348, 22006793). Both aberrant transcripts are expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 28724667, 33471991) and in the compound heterozygous state in individuals affected with ataxia-telangiectasia (PMID: 10330348, 12552559, 22006793). This variant has also been identified in 1/251002 chromosomes 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. -
Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
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The p.R250* pathogenic mutation (also known as c.748C>T), located in coding exon 6 of the ATM gene, results from a C to T substitution at nucleotide position 748. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation has been reported in a cohort of 7657 BRCA1/2-negative Chinese breast cancer patients (Yang Z et al. Breast Cancer Res Treat, 2019 Apr;174:639-647) and in a cohort of 460 individuals from 440 families with at least two primary tumors by age 60 years or at least three by 70 years (Whitworth J et al. Am J Hum Genet, 2018 07;103:3-18). This mutation has been detected in numerous patients with ataxia-telangiectasia (A-T) in conjunction with another pathogenic ATM mutation (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31; Keimling M et al. FASEB J. 2011 Nov;25:3849-60; Nakamura K et al. Hum. Mutat. 2012 Jan;33:198-208). 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. -
Familial cancer of breast Pathogenic:3
This sequence change creates a premature translational stop signal (p.Arg250*) 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 Not observed at a significant frequency in large population cohorts (gnomAD). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and/or breast cancer (PMID: 30816533, 25525159, 12552559, 22006793, 19022408, 10330348, 20840352, 27479817, 21778326, 29909963, 22763152, 30607632, 32521533, 28724667, 32427313, 35664542, 31472684, 34954471, 30697212, 35158934). ClinVar contains an entry for this variant (Variation ID: 216024).This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay For these reasons, this variant has been classified as Pathogenic. -
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This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
ATM-related cancer predisposition Pathogenic:2
The c.748C>T (p.Arg250*) variant in ATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in numerous individuals with Ataxia-Telangiectasia (PMIDs: 10330348, 12552559, 20840352, 21778326, 22006793, 26896185, 30816533, 31611883). The highest population minor allele frequency in gnomAD v2.1.1 0.00003 (1/34560) which meets the PM2 threshold of n≤1 alleles when sub-population frequency is >0.00001 (PM2_Supporting met). In summary, this variant meets criteria to be classified as pathogenic 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. (PVS1, PM5_Supporting, PM3_VeryStrong, PM2_Supporting) -
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not provided Pathogenic:2
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30816533, 25525159, 12552559, 22006793, 19022408, 10330348, 20840352, 27479817, 21778326, 29909963, 22763152, 30607632, 32521533, 28724667, 32427313, 35664542, 31472684, 34954471, 30697212, 35158934) -
ATM: PVS1, PM2 -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
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Gastric cancer Pathogenic:1
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ATM-related disorder Pathogenic:1
The ATM c.748C>T variant is predicted to result in premature protein termination (p.Arg250*). This variant has been reported as compound heterozygous in individuals with ataxia-telangiectasia and as heterozygous in individuals with breast cancer (Buzin et al 2003. PubMed ID: 12552559; Cao et al 2019. PubMed ID: 30816533; Sun et al 2017. PubMed ID: 28724667; Yang et al. 2019. PubMed ID: 30607632). This variant is reported in 0.0029%% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/216024/). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -
Malignant tumor of breast Pathogenic:1
Variant summary: ATM c.748C>T (p.Arg250X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. At least one publication reports experimental evidence that this variant affects mRNA splicing (Teraoka_1999). The variant allele was found at a frequency of 7.6e-06 in 261978 control chromosomes. c.748C>T has been reported in the literature in individuals affected with Ataxia-Telangiectasia or Breast Cancer (Teraoka_1999, Decker_2017). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at