rs587781511
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong
The NM_000051.4(ATM):c.967A>G(p.Ile323Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I323K) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
ATM
NM_000051.4 missense
NM_000051.4 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 5.75
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 11-108247029-A-G is Pathogenic according to our data. Variant chr11-108247029-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108247029-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.967A>G | p.Ile323Val | missense_variant | 8/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.967A>G | p.Ile323Val | missense_variant | 8/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
1
AN:
152246
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251086Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135744
GnomAD3 exomes
AF:
AC:
2
AN:
251086
Hom.:
AF XY:
AC XY:
1
AN XY:
135744
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461144Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 726916
GnomAD4 exome
AF:
AC:
7
AN:
1461144
Hom.:
Cov.:
30
AF XY:
AC XY:
4
AN XY:
726916
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74380
GnomAD4 genome
AF:
AC:
1
AN:
152246
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74380
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 323 of the ATM protein (p.Ile323Val). RNA analysis indicates that this missense change induces altered splicing and likely results in the loss of 101 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs587781511, gnomAD 0.003%). This missense change has been observed in individuals with ataxia telangiectasia (PMID: 10817650, 23652012, 27664052, 31050087). ClinVar contains an entry for this variant (Variation ID: 141123). 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. Studies have shown that this missense change results in the activation of a cryptic splice site in exon 8 (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 28, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Apr 07, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 03, 2023 | This c.967A>G variant is predicted to replace isoleucine with valine at codon 323 of the ATM protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing by creating a new splice donor site. An RNA study using cells from a homozygous individual has shown that this variant results in two transcripts: the major one with an out-of-frame deletion including 99 bases of exon 8 and the entire exon 9 (r.967_1235del, p.Ile323Alafs*17) and the minor transcript with only in-frame deletion of 99 bases of exon 8 (r.967_1065del, p.Ile323_Gln355del) (PMID: 31050087). The transcript with the r.967A>G (p.Ile323Val) missense variant was not detected in this study, indicating almost complete splicing defect due to the c.967A>G variant. This variant has been reported in multiple individuals affected with ataxia telangiectasia in compound heterozygous state with another pathogenic variant (PMID: 10817650, 23652012, 27664052) or in homozygous state (PMID: 31050087). This variant has been identified in 2/251086 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 17, 2023 | The c.967A>G variant (also known as p.I323V), located in coding exon 7 of the ATM gene, results from an A to G substitution at nucleotide position 967. The isoleucine at codon 323 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected both as the only mutation and in conjunction with a second mutation in individuals diagnosed with ataxia-telangiectasia (AT) (Li M et al. Am J Med Genet. 2000; 92:170-7; Lee P. et al. Nat Commun. 2013;4:1824; Carranza D. et al. Neuromolecular Med. 2017 Mar;19(1):161-174; Berland et al J Allergy Clin Immunol 2019 01;143(1):325-334.e2). This variant was also detected in one individual diagnosed with ovarian cancer (Sugino et al Sci Rep 2019 11;9(1):17808) and one individual diagnosed with pancreatic cancer (Cremin et al Cancer Med 2020 06;9(11):4004-4013). Functional analyses of cells generated from individuals diagnosed with AT with this alteration have shown loss of ATM protein and defects in DNA repair or survival following ionizing radiation (Lee P. et al. Nat Commun. 2013;4:1824; Carranza D. et al. Neuromolecular Med. 2017 Mar;19(1):161-174). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 06, 2022 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 13, 2023 | Patient-derived cells from a homozygous A-T patient, also harboring another homozygous ATM variant, demonstrated aberrant splicing, resulting an out-of-frame transcript leading to protein truncation (Fievet et al., 2019); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23652012, 22529920, 26659599, 24145436, 10817650, 26246501, 31050087, 29906526, 27664052, 35245693, 31780705, 32255556) - |
Familial cancer of breast Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 11, 2024 | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10817650, 27664052]. Functional studies indicate this variant impacts protein function [PMID: 27664052]. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;.
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
0.98
.;D;D
Vest4
0.17, 0.15
MutPred
Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP
MPC
0.14
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at