This variant was interpreted by pipeline
7.1.5.
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11.0.02.
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ATM encodes a kinase that acts as a master controller of the cellular DNA damage response: it detects double-strand breaks and coordinates DNA repair, cell cycle arrest, or apoptosis through downstream targets including p53, BRCA1, and CHK2. Loss-of-function mutations in both copies of ATM cause ataxia telangiectasia, an autosomal recessive disorder characterized by neurological problems, immune deficiency, and cancer predisposition. ATM functions as a tumor suppressor: individuals with ataxia telangiectasia are prone to childhood lymphomas, leukemias, and breast cancer, while carriers of a single altered copy have increased risk of breast, pancreatic, prostate, and other cancers. Somatic ATM mutations also occur in lymphoid malignancies and solid tumors, and ATM-deficient cancers are often especially sensitive to DNA-damaging treatments.
This variant
ATM is a tumor suppressor whose loss causes ataxia telangiectasia and, in single-copy carriers, raises risks of breast, pancreatic, and other cancers. This c.7243G>C change (p.Ala2415Pro) is a VUS: it is a rare missense alteration, so whether it impairs ATM's DNA-damage-response function, and any resulting cancer risk, remains uncertain.
Transcript
NM_000051.4
HGVS · transcript:coding
NM_000051.4:c.7243G>C
GRCh38
chr11:108329174 G>C
GRCh37
chr11:108199901 G>C
Applying the ATM VCEP v1.5 framework, the only applied criterion is PM2 (supporting), which alone satisfies no pathogenic or benign combination rule, yielding a VUS.
Classification rationale
PM2VUS
ATM c.7243G>Cmissense · exon 49
PM2 (Supporting): the variant is absent from gnomAD v4.1, exceeding the <=0.001% supporting rarity threshold. Final classification: VUS - PM2 (supporting) alone satisfies no pathogenic or benign combination rule in the ATM VCEP v1.5 framework.
PM2→VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATMNM_000051.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ATM—click a row to locate it on the plot · use the link column to open its page
Protein
Location
Classification
Link
Applied criteria · 1 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength Supporting Moderate Strong Very strong
✓
PM2supportingPathogenic
Met (supporting): the variant is absent from gnomAD v4.1, exceeding the VCEP's <=0.001% supporting rarity threshold.
ClinGen HBOP ATM VCEP v1.5 specifies PM2_Supporting at frequency <=0.001% in the gnomAD v4 dataset and states that n=1 in a single subpopulation is sufficiently rare.The exact variant NM_000051.4:c.7243G>C (NC_000011.10:g.108329174G>C) is absent from gnomAD v4.1; no population allele count or frequency is reported, and the variant therefore does not exceed the PM2 frequency ceiling.The exact variant is also reported as absent from gnomAD v2.1 and gnomAD-Canada v1.0, providing concordant population rarity observations.
Assessed · not applied
· 9 not met · 5 not assessed
Pathogenic
PVS1Not met: c.7243G>C is a missense change (p.Ala2415Pro), not a null variant, and SpliceAI's max delta of 0.012 indicates no splice impact.
PS1Not assessed: no established pathogenic variant producing the same amino-acid change, p.Ala2415Pro, was available for comparison.
PS3Not assessed: a prime-editing screen scored this variant Non-functional, but PS3 awaits human review because that assay is not among the ATM VCEP's calibrated assays.
PS4Not assessed: no case-control enrichment data for this exact variant met the required odds ratio >=2 with p<=0.05.
PM3Not assessed: no proband phenotype, second ATM variant, zygosity, or phase data were available to score under the PM3 points framework.
PM4Not met: PM4 applies only to stop-loss variants, and p.Ala2415Pro is a missense substitution with no protein-length change.
PP3Not met: REVEL 0.512 falls below the ATM VCEP PP3 threshold of >0.7333.
PP5Not met: the sole ClinVar record is a single-submitter Uncertain significance from Ambry, with no expert-panel pathogenic assertion.
Benign
BA1Not met: the variant is absent from gnomAD v4.1, so the >0.5% BA1 allele-frequency threshold is not reached.
BS1Not met: the variant is absent from gnomAD v4.1, so the >0.05% BS1 allele-frequency threshold is not reached.
BS3Not met: the direct functional assay scored the variant Non-functional, showing no rescue of ATM function.
BP2Not assessed: no unaffected-individual or in-trans allele data were available to score under the BP2 points framework.
BP4Not met: REVEL 0.512 exceeds the <=0.249 BP4 threshold required for missense variants.
BP6Not met: the sole ClinVar submission is a single-submitter Uncertain significance, with no expert-panel benign assertion to support BP6.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
Triaged references · 1 PMID not cited in assessment
25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.CLINVAR
