Variant classification summary

NM_000051.4:c.8261C>T

ATM · NP_000042.3:p.(Thr2754Ile) · NM_000051.4

GRCh37: chr11:108206681 C>T · GRCh38: chr11:108335954 C>T

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Thr2754Ile)

gnomAD AF

2.491817494303082e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.8261C>T (p.Thr2754Ile) is a missense variant in ATM, a gene for which loss of function is an established mechanism of disease in ataxia-telangiectasia and in which germline variants confer susceptibility to breast, ovarian, and pancreatic cancer (ClinGen HBOP VCEP v1.5.0).

2

This variant is present at extremely low frequency in population databases: gnomAD v4.1 reports 4 heterozygous carriers among 1,605,254 alleles (total AF=2.49e-06; grpmax FAF=2.8e-07) with no homozygotes observed, and gnomAD v2.1 reports 1 heterozygous carrier among 31,352 alleles (AF=3.19e-05). It is absent from gnomAD-Canada v1.0.

3

In silico predictors are inconclusive: REVEL score is 0.633 (below the ATM VCEP PP3 threshold of >0.7333 but above the BP4 threshold of ≤0.249), BayesDel score is -0.0763065, and SpliceAI predicts no significant splice impact (max delta score = 0.01).

4

This variant has been reported in ClinVar as Uncertain Significance by 6 clinical laboratories (ClinVar Variation ID: 127457), with no expert panel classifications available. No functional studies, case-control analyses, segregation data, or observations in trans with pathogenic ATM variants have been identified for this specific variant.

5

The variant is absent from COSMIC (no somatic cancer reports) and does not fall within a statistically significant Cancer Hotspot. OncoKB reports no reviewed functional evidence and classifies this variant as having Unknown Oncogenic Effect.

6

Under the ClinGen HBOP VCEP for ATM v1.5.0, only PM2_Supporting is met (allele frequency ≤0.001% in gnomAD v4). All other applicable criteria are either not met or not applicable. With a single supporting-level pathogenic criterion and no benign criteria met, the variant is classified as Uncertain Significance (VUS) per the ACMG/AMP 2015 combining rules as adopted by the ATM VCEP.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.5.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is not applicable to missense variants. This variant (NM_000051.4:c.8261C>T, p.Thr2754Ile) is a missense substitution; the ATM VCEP PVS1 decision tree applies only to null variants (nonsense, frameshift, canonical splice, initiation codon, or exon deletions).	pvs1_gene_context pvs1_variant_assessment vcep_atm_pvs1_1_5
PS1	Not met	PS1 requires a known pathogenic missense variant at the same amino acid residue (p.Thr2754) with a different nucleotide change, and splicing must be ruled out for both. SpliceAI max delta score of 0.01 rules out splicing impact. However, no pathogenic missense comparator at p.Thr2754 has been identified through PM5 candidate review or ClinVar search.	spliceai pm5_candidates vcep_atm_ps1_1_5
PS2	N/A	PS2 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
PS3	Not met	No variant-specific functional assay data are available for NM_000051.4:c.8261C>T (p.Thr2754Ile). The ATM VCEP requires demonstration that the variant fails to rescue ATM-specific functional features (e.g., phosphorylation of ATM-specific targets) and/or radiosensitivity. OncoKB reports no reviewed functional evidence for this variant, and no publications with functional data for this exact variant were identified.	oncokb
PS4	Not met	The ATM VCEP requires a formal case-control study with p-value ≤0.05 and an odds ratio/hazard ratio/relative risk ≥2 or lower 95% CI ≥1.5. No case-control study evaluating this variant's enrichment in ATM-associated cancer or ataxia-telangiectasia cohorts has been identified. The variant is extremely rare in population databases (gnomAD v4.1 AF=2.49e-06), but without case counts, PS4 cannot be applied.	gnomad_v4
PS5	Not met	No de novo observations with confirmed maternity and paternity have been reported for this variant. Under generic ACMG/AMP 2015 rules, PS5 is a supporting-level pathogenic criterion applicable when a de novo observation has been confirmed. No such evidence was found in ClinVar submissions, literature, or database searches.
PM1	N/A	PM1 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
PM2	Met	This variant is present at extremely low frequency in gnomAD v4.1 (total AF=2.49e-06; 4/1,605,254 alleles; grpmax FAF=2.8e-07; 0 homozygotes), meeting the ATM VCEP PM2_Supporting threshold of ≤0.001% (≤0.00001) in the gnomAD v4 dataset.	gnomad_v4
PM3	Not met	No evidence of this variant detected in trans with a known pathogenic ATM variant in an individual with ataxia-telangiectasia (A-T) was identified. The ATM VCEP PM3/BP2 framework assigns points based on confirmed trans configuration in A-T probands with confident or consistent phenotype. No such reports were found in ClinVar, literature, or database searches.	vcep_atm_pm3_bp2_1_5
PM4	N/A	The ATM VCEP restricts PM4 to stop-loss variants. NM_000051.4:c.8261C>T is a missense variant (p.Thr2754Ile), not a stop-loss.	cspec
PM5	N/A	The ATM VCEP PM5 specification applies to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, and to splice variants with PVS1_VS(RNA) where NMD is predicted. This is a missense variant (p.Thr2754Ile) and does not fall into these categories. Classic same-residue missense PM5 is not applied under the ATM VCEP framework.	cspec pm5_candidates
PM6	N/A	PM6 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
PP1	Not met	No cosegregation data are available for this variant. Under the ATM VCEP, PP1 applies to autosomal recessive conditions (ataxia-telangiectasia) and requires segregation in affected relatives (1=Supporting, 2=Moderate, ≥3=Strong). No family studies or segregation analyses involving this variant have been identified.
PP2	N/A	PP2 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
PP3	Not met	The REVEL score for this missense variant is 0.633, which is below the ATM VCEP PP3 threshold of >0.7333. The BayesDel score is -0.0763065. SpliceAI predicts no significant splice impact (max delta score = 0.01, below the 0.2 threshold). None of the ATM VCEP in silico criteria for PP3 are satisfied.	spliceai revel bayesdel
PP4	N/A	PP4 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
PP5	N/A	PP5 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
BA1	Not met	The ATM VCEP BA1 threshold requires a grpmax filtering allele frequency >0.5% in gnomAD v4. The observed grpmax FAF is 2.8e-07 (0.000028%), which is far below the 0.5% stand-alone benign threshold.	gnomad_v4
BS1	Not met	The ATM VCEP BS1 threshold requires a grpmax filtering allele frequency >0.05% in gnomAD v4. The observed grpmax FAF is 2.8e-07 (0.000028%), which is well below the 0.05% strong benign threshold.	gnomad_v4
BS2	N/A	BS2 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
BS3	Not met	No functional evidence demonstrating that this variant rescues ATM-specific function (e.g., phosphorylation of ATM-specific targets) or radiosensitivity has been identified. The ATM VCEP BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. OncoKB contains no reviewed functional evidence for this variant.	oncokb
BS4	N/A	BS4 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
BP1	N/A	BP1 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
BP2	Not met	No evidence of this variant occurring in trans with a known pathogenic ATM variant in an unaffected (non-A-T) individual has been identified. The ATM VCEP BP2 framework assigns negative points for observations of the variant in trans with pathogenic variants in healthy individuals. No such observations are available in ClinVar, gnomAD homozygote data, or published literature.	gnomad_v4 gnomad_v2 vcep_atm_pm3_bp2_1_5
BP3	N/A	BP3 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
BP4	Not met	The ATM VCEP BP4 missense threshold requires a REVEL score ≤0.249. This variant has a REVEL score of 0.633, which exceeds the threshold. While SpliceAI predicts no splice impact (max delta=0.01, ≤0.1 meets the splicing BP4 criterion), the missense BP4 criterion takes precedence for a missense variant and is not met.	spliceai revel bayesdel
BP5	N/A	BP5 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
BP6	N/A	BP6 is listed as Not Applicable by the ClinGen HBOP VCEP for ATM v1.5.0.	cspec
BP7	N/A	BP7 is restricted to synonymous and deep intronic variants per the ATM VCEP specification. NM_000051.4:c.8261C>T is a missense variant (p.Thr2754Ile) and does not qualify for BP7 assessment.	cspec

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