GeneBe

rs1555068609

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.1058_1059delGT​(p.Cys353SerfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,448 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C353C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATM
NM_000051.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.26

Publications

1 publications found
Variant links:
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):
  • ATM-related cancer predisposition
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • hereditary breast carcinoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
  • ataxia telangiectasia
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine
  • prostate cancer
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • sarcoma
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • gastric carcinoma
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
  • hereditary nonpolyposis colon cancer
    Inheritance: 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 11-108247118-CTG-C is Pathogenic according to our data. Variant chr11-108247118-CTG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 490410.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

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
ATM
NM_000051.4
MANE Select
c.1058_1059delGTp.Cys353SerfsTer5
frameshift
Exon 8 of 63NP_000042.3
ATM
NM_001351834.2
c.1058_1059delGTp.Cys353SerfsTer5
frameshift
Exon 9 of 64NP_001338763.1Q13315

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
ATM
ENST00000675843.1
MANE Select
c.1058_1059delGTp.Cys353SerfsTer5
frameshift
Exon 8 of 63ENSP00000501606.1Q13315
ATM
ENST00000452508.7
TSL:1
c.1058_1059delGTp.Cys353SerfsTer5
frameshift
Exon 9 of 64ENSP00000388058.2Q13315
ATM
ENST00000531525.3
TSL:1
c.1058_1059delGTp.Cys353SerfsTer5
frameshift
Exon 8 of 30ENSP00000434327.3H0YDU7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461448
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
727020
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33458
American (AMR)
AF:
0.00
AC:
0
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26120
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39620
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86198
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53404
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111796
Other (OTH)
AF:
0.00
AC:
0
AN:
60378
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
2
-
-
Hereditary cancer-predisposing syndrome (2)
1
-
-
Ataxia-telangiectasia syndrome (1)
1
-
-
Familial cancer of breast (1)
1
-
-
not provided (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
9.3
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1555068609; hg19: chr11-108117845; COSMIC: COSV53744515; API