rs786203606
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePP5_Very_Strong
The NM_000051.4(ATM):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000062 in 1,613,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
ATM
NM_000051.4 start_lost
NM_000051.4 start_lost
Scores
7
6
2
Clinical Significance
Conservation
PhyloP100: 7.17
Genes affected
ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_000051.4 (ATM) was described as [Likely_pathogenic] in ClinVar as 188901
PP5
?
Variant 11-108227626-T-C is Pathogenic according to our data. Variant chr11-108227626-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 187275.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-108227626-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.2T>C | p.Met1? | start_lost | 2/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2T>C | p.Met1? | start_lost | 2/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251392Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135870
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461386Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 727046
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 25, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | GeneReviews | Oct 27, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change affects the initiator methionine of the ATM mRNA. The next in-frame methionine is located at codon 94. This variant is present in population databases (rs786203606, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individual(s) with ataxia-telangiectasia (PMID: 8845835, 9463314, 12552559, 21792198, 22649200). 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: 187275). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects ATM function (PMID: 21593342, 21792198, 22146522). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 29, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 26, 2019 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 19, 2021 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is expected to interfere with initiation of protein synthesis. In multiple individuals affected with ataxia-telangiectasia (A-T), this variant has been seen with another recessive pathogenic variant in the same gene. At least one other variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies demonstrate either low levels of ATM protein (PMID:22146522, 21459046, 22649200) or no ATM protein (PMID:9463314) with no kinase activity. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2022 | Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in the heterozygous state in individuals with breast, prostate, and other cancers (Crawford et al., 2017; Decker et al., 2017; Gardner et al., 2018; Waszak et al., 2018; Zafeiriou et al., 2019); Published functional studies demonstrate the possible use of a downstream initiation codon, resulting in trace levels of a truncated protein with no kinase activity, while other studies have shown completely absent protein production (Stankovic et al., 1998; Exley et al., 2011; Reiman et al., 2011; Byrd et al., 2012; Carney et al., 2012); This variant is associated with the following publications: (PMID: 26898890, 28281021, 22649200, 18174244, 28779002, 8845835, 21681852, 22146522, 21593342, 21792198, 9463314, 12552559, 29753700, 30340782, 29308099, 30549301, 30322717, 29922827, 26896183, 21459046) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2024 | The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the ATM gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This alteration has been reported in individuals with ovarian cancer (Crawford B et al. Breast Cancer Res. Treat., 2017 Jun;163:383-390; Carter NJ et al. Gynecol. Oncol., 2018 12;151(3):481-488), in an individual with medulloblastoma (Waszak SM et al. Lancet Oncol., 2018 06;19(6):785-798), and in an individual with prostate cancer (Zafeiriou Z et al. Eur. Urol., 2019 01;75(1):184-192). This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B at al. J. Med. Genet., 2017 11;54(11):732-741). This alteration has also been reported in a compound heterozygous state in multiple patients with ataxia telangiectasia (Gilad S et al. Hum. Mol. Genet., 1996 Apr;5:433-9; Stankovic T et al. Am. J. Hum. Genet., 1998 Feb;62(2):334-45; Buzin CH et al. Hum. Mutat., 2003 Feb;21:123-31; Reiman A et al. Br. J. Cancer, 2011 Aug;105(4):586-91; Byrd PJ et al. Br. J. Cancer, 2012 Jan;106:262-8; Schon et al. Ann. Neurol., 2019 02;85(2):170-180; Byrd et al. Nature 2023 Jul;619(7971):828-836). 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, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 10, 2022 | This variant results in the loss of the translation start codon (methionine at codon 1) of the ATM gene. This variant is expected to disrupt the expression of the full-length ATM protein. The next in-frame methionine occurs at codon 94, but it has not been shown if a functional ATM protein product can be produced using p.Met94 as an alternative translation start site. This variant has been reported in over ten individuals affected with ataxia-telangiectasia in compound heterozygous state with pathogenic mutations (PMID: 8845835, 9463314, 12552559, 15928302, 21593342, 21792198, 22146522, 22649200, 30549301). In cell lines derived from these individuals, a very low level of expression of a truncated ATM protein was observed, probably due to the use of an alternate downstream methionine (PMID: 21593342, 21792198, 22146522). There was no detectable kinase activity in these cell lines. This variant has also been observed in individuals affected with breast cancer (PMID: 28779002, 29308099), ovarian cancer (PMID: 28281021) and brain cancer (PMID: 29753700). This variant has been identified in 1/251392 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 10, 2024 | This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21665257, 9463314, 21792198, 12552559, 22649200, 22146522, 30549301]. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen | Mar 16, 2022 | The ATM c.2T>C (p.M1?) variant impacts the initiation codon and is not expected to produce a fully functional protein (PVS1). This variant has been observed in a compound heterozygous state in multiple individuals with Ataxia-Telangiectasia (PMIDs: 22146522, 3054930, 12552559, PM3_VeryStrong). This alteration has an allele frequency below 0.001% in the European (non-Finnish) subpopulation in GnomAD (PM2_Supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel. - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 04-23-2015 by Lab Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.;.;.;.;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PROVEAN
Uncertain
D;N;D;D;.;N;.;.;.;.;.
REVEL
Uncertain
Sift
Pathogenic
D;D;D;D;.;D;.;.;.;.;.
Sift4G
Pathogenic
D;D;D;D;D;D;.;.;.;D;D
Polyphen
0.87, 0.96
.;P;.;.;.;P;P;P;P;P;.
Vest4
0.95, 0.91, 0.96, 0.96
MutPred
Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);Gain of catalytic residue at M1 (P = 0.0046);
MVP
ClinPred
D
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RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at