rs786201957
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000051.4(ATM):c.3349C>T(p.Gln1117Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000411 in 1,461,504 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. Q1117Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000051.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.3349C>T | p.Gln1117Ter | stop_gained | 23/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.3349C>T | p.Gln1117Ter | stop_gained | 23/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461504Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727056
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 185137). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 16832357). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1117*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2023 | The p.Q1117* pathogenic mutation (also known as c.3349C>T), located in coding exon 22 of the ATM gene, results from a C to T substitution at nucleotide position 3349. This changes the amino acid from a glutamine to a stop codon within coding exon 22. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was identified in conjunction with a pathogenic variant in ATM in 1 individual from the UK diagnosed with ataxia-telangiectasia (Jackson TJ et al. Dev Med Child Neurol 2016 Jul;58(7):690-7). This alteration has also been detected in breast cancer patients and healthy control individuals across numerous large familial studies (Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46; Renwick A et al. Nat Genet, 2006 Aug;38:873-5). As such, this alteration is interpreted as a disease-causing mutation. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 22, 2024 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at