chr11-108289759-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3_StrongPM2_SupportingPP3
This summary comes from the ClinGen Evidence Repository: The c.4394T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 1465 (p.Leu1465Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001% in European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (LINK:https://erepo.genome.network/evrepo/ui/classification/CA298357/MONDO:0016419/020
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4394T>C | p.Leu1465Pro | missense_variant | 29/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.4394T>C | p.Leu1465Pro | missense_variant | 29/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251106Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135722
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461230Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726930
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 30, 2015 | Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size and hydrophobic Leucine (L) with a medium size and hydrophobic Proline (P). 4/4 in silico tools predict damaging outcome for this substitution. Variant was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.00084% which does not exceed the maximal expected allele frequency of a disease causing ATM variant (0.4%). The variant was reported in one A-T patient (Izatt_EJHG_1999) who was compound heterozygote for the variant of interest and a potentially deleterious frameshift/truncating variant 1355delC; p.Thr452Asnfs indicating the variant to have a role in A-T pathology. Furthermore, Izatt_EJHG_1999 showed the variant to result in low level of ATM expression indicating that the L1465P missense mutation may lead to instability of the protein. Additionally, Barone_Hum Mutat_2009 reported the L1465P ATM variant to have reduced kinase activity toward its downstream targets providing an independent support for the pathogenicity of the variant. A clinical laboratory classifies variant as Likely Pathogenic via ClinVar (without evidence to independently evaluate) and HGMD lists variant with a classification of Disease Mutation. Considering all evidence, the variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 06, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 28, 2022 | 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. Experimental studies have shown that this missense change affects ATM function (PMID: 10234507, 19431188). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1465 of the ATM protein (p.Leu1465Pro). This variant is present in population databases (rs730881391, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of ataxia-telangiectasia, esophageal cancer, gastric cancer, and/or prostate cancer (PMID: 10234507, 26681312, 26896183, 32853339, 33436325). 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: 181996). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function. - |
Familial cancer of breast Pathogenic:2
Likely pathogenic, reviewed by expert panel | curation | ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen | Jan 25, 2024 | The c.4394T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 1465 (p.Leu1465Pro). The highest population minor allele frequency in gnomAD v2.1.1 is 0.001% in European (non-Finnish) population, which is lower than the ClinGen HBOP threshold (</=0.001%) for PM2_Supporting, meeting this criterion. This variant has been detected in at least one individual with Ataxia-Telangiectasia (PMID 9463314, 10234507, 26896183). The computational predictor, Revel (Score: 0.802), predicts a damaging effect on ATM function. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP (PM2_supporting, PM3_strong, PP3). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 12, 2023 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 03, 2023 | Published functional studies demonstrate reduced kinase activity (Barone et al., 2009); Identified in individuals with breast or prostate cancer and segregates with disease in at least one family (Darst et al., 2021; Karlsson et al., 2021; Lourenco et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27304073, 22529920, 26681312, 29308099, 29922827, 10234507, 26896183, 27153395, 33436325, 32853339, 19431188, 37232349) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 13, 2023 | The p.L1465P variant (also known as c.4394T>C), located in coding exon 28 of the ATM gene, results from a T to C substitution at nucleotide position 4394. The leucine at codon 1465 is replaced by proline, an amino acid with very few similar properties. This variant has been reported in the literature in a compound heterozygous state in an Irish individual with Ataxia-Telangiectasia (A-T). Functional analysis indicated low levels of ATM expression (1%) suggesting that this alteration likely changes the secondary structure of the protein as the proline substitution is located in the middle of a predicted α-helix from amino acids 1460 to 1476 (Izatt L et al. Eur. J. Hum. Genet. 1999 Apr; 7(3):310-20). An additional report suggests this alteration results in reduced kinase activity. Authors note that 8 of the 10 ATM variants in this study with reduced kinase activity were identified in A-T patients with a milder A-T phenotype, but do not specify which 8 (Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel. This individual had a personal history of esophageal and gastric cancers (Susswein LR et al. Genet. Med. 2016 08;18:823-32). This variant was reported in 10/5560 prostate cancer cases and in 2/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol. 2021 Aug;4:570-579). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability; however, the impact on protein function is not clear (Ambry internal data; Bareti D et al. Sci Adv. 2017 May;3(5):e1700933). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at