rs587781927
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000051.4(ATM):c.4776+2T>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000137 in 1,455,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000051.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.4776+2T>A | splice_donor_variant, intron_variant | Intron 31 of 62 | ENST00000675843.1 | NP_000042.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1455110Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 724322
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Ataxia-telangiectasia syndrome Pathogenic:3
This sequence change affects a donor splice site in intron 31 of the ATM gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with ATM-related conditions (PMID: 9497252, 9600235, 12815592, 31214711, 32566746). ClinVar contains an entry for this variant (Variation ID: 371007). Studies have shown that disruption of this splice site results in skipping of exon 31, also published as exon 33, but is expected to preserve the integrity of the reading-frame (PMID: 9711876). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: ATM c.4776+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by published functional studies although one report provided indirect evidence supporting the skipping of exon 30 (legacy naming as exon 33) without presenting the data (Sasaki_1998). The variant was absent in 249594 control chromosomes. c.4776+2T>A (reported as 4612del165 or IVS33+2T>A) has been reported in the literature in multiple homozygous and compound heterozygous individuals of Japanese ancestry affected with Ataxia-Telangiectasia (example, Ejima_1998, Sasaki_1998) as well as in reports of Japanese carriers with breast cancer (example, Kaneyasu_2020, Momozawa_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories and one research foundation have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic (n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Familial cancer of breast Pathogenic:2
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This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant causes a T to A nucleotide substitution at the +2 position of intron 31 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a number of unrelated Japanese individuals affected with breast cancer (PMID: 32566746, 30287823), pancreatic cancer (PMID: 32980694; Color Health internal data), prostate cancer (PMID: 31214711), ataxia-telangiectasia (PMID: 9600235, 9711876), as well as in healthy controls (PMID: 30287823, 32980694). This variant has not been identified 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 Likely Pathogenic. -
The c.4776+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 30 in the ATM gene. This alteration was seen in multiple, unrelated Japanese patients with ataxia-telangiectasia, and RNA analysis demonstrated that it results in skipping of coding exon 30 (designated as exon 33 in this study) (Ejima Y et al. Hum. Genet., 1998 Apr;102:403-8). In addition, a different ATM mutation at this nucleotide position, c.4776+2T>C, was also seen in patients with ataxia-telangiectasia and was also shown to result in skipping of coding exon 30 (Gilad S et al. Am. J. Hum. Genet. 1998 Mar;62(3):551-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). As such, this alteration is classified as a disease-causing mutation. -
Gastric cancer Pathogenic:1
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Hereditary breast ovarian cancer syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at