11-108312424-G-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000051.4(ATM):c.5932G>T(p.Glu1978*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,595,290 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 (★★). 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.5932G>T | p.Glu1978* | stop_gained | Exon 40 of 63 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000438 AC: 11AN: 251182Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135808
GnomAD4 exome AF: 0.0000152 AC: 22AN: 1443140Hom.: 0 Cov.: 29 AF XY: 0.0000139 AC XY: 10AN XY: 719082
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74350
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:8
This sequence change creates a premature translational stop signal (p.Glu1978*) 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). This variant is present in population databases (rs587779852, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast cancer (PMID: 15880721, 16266405, 17124347, 18497957, 18807267, 19691550, 25614872). ClinVar contains an entry for this variant (Variation ID: 127414). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -
- -
Variant summary: The ATM c.5932G>T (p.Glu1978X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.7327C>T [p.Arg2443X], c.7517_7520delGAGA [p.Arg2506fsX3], and c.7913G>A [p.Trp2638X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the control database ExAC and control cohorts reported in the literature at a frequency of 0.0000779 (10/128320 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). The variant has been found in homozygosity and compound heterozygosity in numerous patients and families with ataxia-telangiectasia (Podralska_MGGM_2014; Birrell_HM_2005). Additionally, a large case-control study showed that the variant is enriched in heterozygous breast cancer patients in Eastern European populations (Odds Ratio = 5.6; 95% CI = 1.323.4; p = 0.01; Bogdanova_BCRT_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic for both ataxia-telangiectasia and hereditary cancer. Taken together, this variant is classified as pathogenic. -
- -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000127414 / PMID: 9443866). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
- -
- -
Data included in classification: Truncating nonsense variant with frameshift (https://doi.org/10.1007/s10549-008-0189-9) (PVS1_vstr) Bogdanova et al 2008 (https://doi.org/10.1007/s10549-008-0189-9) Mantel–Haenszel Odds Ratio (OR): 5.6, 95% CI: 1.3–21.4, P = 0.01 - p ≤0.05 and OR is above 2 (PS4_str) Termination at a codon prior to p.Arg3047 (PM5_sup) Identified in 8/32 alleles in probands with ataxia telangiectasia (https://doi.org/10.1002/humu.9341) Observations in multiple ataxia telangiectasia cases (PMID: 15880721, 16266405, 17124347, 18807267, 19691550, 25614872, 18497957) (PM3_vstr) Data not included in classification: Multiple classification as pathogenic in ClinVar Allele frequency in Non-Finnish Europeans (NFE), gnomAD v2.1 Jan 2019: 5/102582 (0.005%). Variant frequency is at a frequency of ≥0.001%. -
Familial cancer of breast Pathogenic:8
- -
- -
Criteria applied: PVS1,PM5 -
PVS1, PS3_MOD, PM3_VSTR -
ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderated, PM3 moderated -
- -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
- -
not provided Pathogenic:7
Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a known mechanism of disease (Telatar 1998, Teraoka 1999, Mitui 2005, Mort 2014); Observed in the heterozygous state in individuals with ATM-related cancers (Soukupova 2008, Huang 2015, Hu 2016, Pritchard 2016, Yang 2016, Decker 2017, Brand 2018, Isaacsson Velho 2018, Penkert 2018); Case control studies suggest this variant is associated with breast cancer (Bogdanova 2009, Zhang 2011); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26483394, 26681312, 21514219, 24451234, 10817650, 16266405, 9872980, 8808599, 10330348, 19781682, 9443866, 18807267, 18497957, 26380989, 26506520, 25525159, 27112364, 10980530, 27449771, 27433846, 28779002, 29368341, 29625052, 30322717, 30113427, 30549301, 30067863, 30086788, 34426522, 32295079, 15880721, 33077847, 31589614, 33436325, 33726816, 32441320, 27535533) -
DNA sequence analysis of the ATM gene demonstrated a sequence change, c.5932G>T, in exon 40 that results in the creation of a premature stop codon at amino acid position 1978, p.Glu1978*. This variant is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ATM protein with potentially abnormal function. The p.Glu1978* change has been described in the gnomAD database with a frequency of 0.009% in the European sub-population (dbSNP rs587779852) and is a prevalent ATM variant in the Eastern European population (PMIDs: 15880721, 16266405, 18807267). This sequence change has been described in several individuals with ataxia-telangiectasia and breast cancer (PMIDs: 26380989, 30549301, 15880721, 16266405, 25614872, 17124347, 19691550, 18807267, 28779002, 30086788). The p.Glu1978* change has also been observed in individuals with pancreatic cancer, ovarian cancer, gastric cancer, and prostate cancer (PMIDs: 30067863, 27449771, 30322717, 26506520, 29368341). Functional studies have demonstrated skipping of exon 40 in the presence of this sequence change (PMIDs: 9443866, 10330348, 24451234). These collective evidences indicate that this is a pathogenic sequence change. -
- -
- -
ATM: PVS1, PM2, PS4:Moderate, PS3:Supporting -
- -
- -
Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Pathogenic:2Other:1
Variant interpreted as Pathogenic and reported on 08-07-2019 by Lab Invitae. 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. -
- -
ACMG Criteria: PVS1, PS3, PS4, PP5; Variant was found in heterozygous state. -
Breast and/or ovarian cancer Pathogenic:2
- -
- -
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.E1978* mutation (also known as c.5932G>T), located in coding exon 39 of the ATM gene, results from a G to T substitution at nucleotide position 5932. This changes the amino acid from a glutamate to a stop codon within exon 40. This alteration has been reported in multiple individuals with ataxia-telangiectasia from various ethnic backgrounds and is likely a Russian founder mutation (Li A et al. Am. J. Med. Genet. 2000 May;92(3):170-7; Birrell GW et al. Hum. Mutat. 2005 Jun;25(6):593; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64; Podralska MJ et al. Mol. Genet. Genomic Med. 2014 Nov;2(6):504-11). In addition, p.E1978* has been described as a breast cancer susceptibility allele of Eastern European origin (Bogdanova N et al. Breast Cancer Res. Treat. 2009 Nov;118(1):207-11). It was also seen in a patient with prostate cancer with a Gleason score of 9 (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375(5):443-53) and in cohorts of pancreatic cancer patients (Chaffee KG et al. Genet Med. 2018 01;20:119-127; Hu C et al. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25:207-11). This mutation was shown to cause skipping of coding exon 39 (reported as exon 42), as well as a premature truncation in a subset of ATM transcripts (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by aberrant splicing, premature protein truncation, or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
This variant changes 1 nucleotide in exon 40 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has shown significant association with breast cancer in meta-analyses of multiple case-control studies (OR: 5.6, 95% CI: 1.3-21.4, p=0.01; PMID: 18807267) (OR: 4.56, 95% CI: 1.35-15.42, p=0.015; PMID: 21514219). This variant is a common cause of autosomal recessive ataxia-telangiectasia in Eastern Europe (PMID: 10330348, 15880721, 16266405). This variant has been identified in 11/251182 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Ataxia-telangiectasia syndrome;C3469522:Breast cancer, susceptibility to Pathogenic:1
This c.5932G>T (p.Glu1978Ter) variant in exon 41 of the ATM gene creates a premature translational stop signal and is predicted to result in loss of function through nonsense-mediated mRNA decay or by producing a truncated protein. This variant is present in population databases (rs587779852, gnomAD 0.004379%). This variant has been reported in several individuals affected with ataxia-telangiectasia (PMID: 15880721, 16266405, 17124347, 18497957, 19691550, 25614872) and breast cancer (PMID: 18807267). It has been found to be a prevalent ATM mutation in Eastern Europe (PMID: 15880721, 16266405, 18807267). Experimental studies indicate that this nonsense change leads to out-of-frame skipping of exon 41 (PMID: 10330348, 24451234). Therefore, this variant is classified as pathogenic. -
ATM-related disorder Pathogenic:1
The ATM c.5932G>T variant is predicted to result in premature protein termination (p.Glu1978*). This variant has previously been reported by several studies in individuals with ataxia telangiectasia (Telatar et al 1998. PubMed ID: 9443866; Birrell et al. 2005. PubMed ID: 15880721; Mitui et al. 2005. PubMed ID: 16266405). This variant is also associated with breast cancer susceptibility (Bogdanova et al. 2009. PubMed ID: 18807267). This variant is particularly prevalent in families with a history of ataxia telangiectasia and who are of Eastern European decent (specifically Polish and Russian) (Mitui et al. 2005. PubMed ID: 16266405; Birrell et al. 2005. PubMed ID: 15880721). This variant is reported in 0.0088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127414/?new_evidence=true). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at