chr11-108271388-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_000051.4(ATM):c.3059C>T(p.Thr1020Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1020K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.3059C>T | p.Thr1020Ile | missense_variant | 20/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.3059C>T | p.Thr1020Ile | missense_variant | 20/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250920Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135658
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461770Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 6AN XY: 727186
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1020 of the ATM protein (p.Thr1020Ile). This variant is present in population databases (rs186626274, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 220080). 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 tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jul 20, 2022 | The ATM c.3059C>T (p.Thr1020Ile) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. A small case-control study of females with breast cancer indicates that this variant does not have an increased prevalence in cases versus controls (P value = 1.00, OR = 1.2, 95% CI: 0.2-7.1; PMID: 30287823). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 08, 2017 | Variant summary: The ATM c.3059C>T (p.Thr1020Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. This variant is located in the Armadillo-type fold (IPR016024) (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 1/120648 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant was reported in one patient without co-occurrence or co-segregation data. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Due to the paucity of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 27, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Lhota et al., 2016; Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 30287823, 26822949, 27499925, 29685880, 33875564, 19781682) - |
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 10, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 25, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 07, 2022 | This missense variant replaces threonine with isoleucine at codon 1020 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and in healthy controls (PMID: 26822949, 33471991). This variant has been identified in 3/250920 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 26, 2023 | The p.T1020I variant (also known as c.3059C>T), located in coding exon 19 of the ATM gene, results from a C to T substitution at nucleotide position 3059. The threonine at codon 1020 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported with a carrier frequency of 0.00043 in 7051 unselected breast cancer patients and 0.00036 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The ATM p.Thr1020Ile variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, ATM-LOVD, databases. The variant was identified in dbSNP (ID: rs186626274) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx), Clinvitae (classified as uncertain significance by ClinVar, Invitae), databases. The variant was identified in control databases in 3 of 245678 chromosomes at a frequency of 0.000012 (Genome Aggregation Consortium Feb 27, 2017). The p.Thr1020 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. This variant is located within the Armadillo-type Fold unctional domain, increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at