NM_000051.4:c.2135C>G
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000051.4(ATM):c.2135C>G(p.Ser712*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,334 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S712S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
ATM
NM_000051.4 stop_gained
NM_000051.4 stop_gained
Scores
2
4
Clinical Significance
Conservation
PhyloP100: 1.99
Publications
3 publications found
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]
ATM Gene-Disease associations (from GenCC):
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
- ataxia telangiectasiaInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
- prostate cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- familial ovarian cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- gastric carcinomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-108256225-C-G is Pathogenic according to our data. Variant chr11-108256225-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 370600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | NM_000051.4 | MANE Select | c.2135C>G | p.Ser712* | stop_gained | Exon 14 of 63 | NP_000042.3 | ||
| ATM | NM_001351834.2 | c.2135C>G | p.Ser712* | stop_gained | Exon 15 of 64 | NP_001338763.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ATM | ENST00000675843.1 | MANE Select | c.2135C>G | p.Ser712* | stop_gained | Exon 14 of 63 | ENSP00000501606.1 | ||
| ATM | ENST00000452508.7 | TSL:1 | c.2135C>G | p.Ser712* | stop_gained | Exon 15 of 64 | ENSP00000388058.2 | ||
| ATM | ENST00000531525.3 | TSL:1 | c.2135C>G | p.Ser712* | stop_gained | Exon 14 of 30 | ENSP00000434327.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.89e-7 AC: 1AN: 1452334Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 722484 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1452334
Hom.:
Cov.:
30
AF XY:
AC XY:
0
AN XY:
722484
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33356
American (AMR)
AF:
AC:
0
AN:
44532
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25914
East Asian (EAS)
AF:
AC:
0
AN:
39346
South Asian (SAS)
AF:
AC:
0
AN:
84836
European-Finnish (FIN)
AF:
AC:
0
AN:
52680
Middle Eastern (MID)
AF:
AC:
0
AN:
5724
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1106068
Other (OTH)
AF:
AC:
0
AN:
59878
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts