Variant classification summary

NM_000051.4:c.8155C>T

ATM · NP_000042.3:p.(Arg2719Cys) · NM_000051.4

GRCh37: chr11:108206575 C>T · GRCh38: chr11:108335848 C>T

Gene: ATM Transcript: NM_000051.4

Final call

VUS

BS3 supporting benign

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Arg2719Cys)

gnomAD AF

1.2408117887046422e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4(ATM):c.8155C>T (p.Arg2719Cys) is a missense variant in exon 56 of ATM, a gene in which loss of function is an established mechanism for ataxia-telangiectasia (autosomal recessive) and in which pathogenic variants confer moderate risk for hereditary breast, ovarian, and pancreatic cancer.

2

This variant is present in gnomAD v4.1 at an overall allele frequency of 1.24e-05 (20/1,611,848 alleles; 0 homozygotes) with a grpmax filtering allele frequency of 9.55e-06. The allele frequency slightly exceeds the ATM VCEP PM2_Supporting threshold of ≤0.001%, and no subpopulation has a singleton observation.

3

In silico predictors are inconclusive: REVEL score is 0.613 (intermediate, not meeting PP3 threshold of >0.7333 nor BP4 threshold of ≤0.249). BayesDel score is -0.091 (weakly favoring benign). SpliceAI predicts no splicing impact (max delta = 0.03).

4

A comprehensive functional screen of all ATM SNVs by Lee et al. (2025, PMID:40580951, Cell) using saturation prime editing classified p.Arg2719Cys as 'Functional' with 'High' confidence in a PARP inhibitor (olaparib) fitness assay, indicating the variant retains ATM DNA damage response function. Per ATM VCEP v1.5.0, this supports BS3_Supporting (variant rescues an ATM-specific feature).

5

This variant has been reported in ClinVar as Uncertain Significance by 14 clinical laboratories (Variation ID: 185832). No expert panel classification is available. Three ClinVar submissions with criterion-level data (Ambry Genetics, Invitae, Color Health) also classify the variant as Uncertain Significance.

6

This variant has been observed in somatic cancers (COSMIC COSV53736920, n=7), but somatic occurrence does not independently inform germline classification under the ATM VCEP framework.

7

No evidence was found for: a pathogenic missense variant at the same residue (PS1), case-control enrichment (PS4), compound heterozygosity with a pathogenic variant in an A-T patient (PM3), cosegregation with disease (PP1), or observation in trans with a pathogenic variant in an unaffected individual (BP2).

8

Applying the ATM VCEP v1.5.0 criteria, BS3_Supporting is the only criterion met. All pathogenic criteria are either not met or not applicable. Under the ACMG/AMP 2015 combining rules (adopted by the VCEP), one supporting benign criterion without any pathogenic criteria results in an overall classification of Uncertain Significance.

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 applicable to null variants (nonsense, frameshift, canonical splice, initiation codon, exon deletion). NM_000051.4:c.8155C>T is a missense variant (p.Arg2719Cys) and does not fall into any PVS1 null-variant bucket under the ATM VCEP v1.5.0 PVS1 decision tree.	vcep_atm_pvs1_1_5
PS1	Not met	No established pathogenic or likely pathogenic missense variant at the same amino acid residue (Arg2719) was identified. The ATM VCEP PS1 rules require a reference (likely) pathogenic variant at the same nucleotide or same donor/acceptor motif for splicing variants. No qualifying comparator variant was found at this residue.
PS2	N/A	PS2 (de novo) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
PS3	Not met	The ATM VCEP PS3 rules require a variant to fail to rescue ATM-specific function(s). Published functional data from Lee et al. 2025 (PMID:40580951; prime editing screen of all ATM SNVs) classified p.Arg2719Cys as 'Functional' with 'High' confidence, indicating retention of ATM activity rather than loss of function. This evidence supports benign effect (BS3), not pathogenic effect.	PMID:40580951
PS4	Not met	The ATM VCEP PS4 rule requires case-control studies with p-value ≤0.05 and OR ≥2 (or lower 95% CI ≥1.5). No case-control study specifically evaluating NM_000051.4:c.8155C>T was identified. The available literature (PMID:28779002, PMID:33471991) examined ATM truncating variants, not this specific missense variant, and did not provide variant-level case-control data for c.8155C>T.
PS5	N/A	PS5 (same residue as pathogenic variant but different nucleotide change leading to different amino acid) is not defined in the ATM VCEP v1.5.0 criteria; PM5 replaces this criterion in the VCEP specification with a truncation-cutoff rule not applicable to missense variants. Generic PS5 is not assessed because the VCEP framework takes precedence.	cspec
PM1	N/A	PM1 (mutational hot spot or critical functional domain) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
PM2	Not met	The ATM VCEP PM2_Supporting rule requires allele frequency ≤0.001% in gnomAD v4. This variant has an allele frequency of 1.24e-05 (0.00124%, 20/1,611,848 alleles) in gnomAD v4.1, which slightly exceeds the ≤0.001% threshold. No single subpopulation has n=1 (lowest subpopulation count is n=2 in South Asian population), so the n=1 exception does not apply.	gnomad_v4
PM3	Not met	The ATM VCEP PM3 rule requires observation of the variant in trans with a pathogenic variant in probands with ataxia-telangiectasia (A-T). No published case or database entry was identified showing NM_000051.4:c.8155C>T in trans with a known pathogenic ATM variant in an A-T patient. Exploratory search of LOVD and PubMed did not yield qualifying compound heterozygote records.
PM4	N/A	PM4 (protein length changes due to in-frame deletions/insertions or stop-loss) is restricted to stop-loss variants by the ATM VCEP v1.5.0. This is a missense variant and does not qualify.	cspec
PM5	N/A	The ATM VCEP PM5 rule is a truncation-cutoff criterion applied to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or splice variants with NMD-prone PTCs upstream of p.Arg3047. This missense variant does not create a premature termination codon and is not eligible for PM5 under VCEP specifications.	cspec
PM6	N/A	PM6 (assumed de novo) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
PP1	Not met	The ATM VCEP PP1 rule requires cosegregation with disease in families with ataxia-telangiectasia (AR condition: 1 affected relative = supporting, 2 = moderate, ≥3 = strong). No published family study or segregation data involving NM_000051.4:c.8155C>T was identified.
PP2	N/A	PP2 (missense in gene with low rate of benign missense) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
PP3	Not met	The ATM VCEP PP3 rule for missense variants requires REVEL >0.7333. The REVEL score for this variant is 0.613, which does not meet the threshold. For splicing prediction, PP3 requires SpliceAI ≥0.2; the SpliceAI max delta score is 0.03, which also does not meet the threshold.	revel spliceai
PP4	N/A	PP4 (patient phenotype or family history highly specific for gene) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
PP5	N/A	PP5 (reputable source reports variant as pathogenic) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
BA1	Not met	The ATM VCEP BA1 rule requires a grpmax filtering allele frequency >0.5% in gnomAD v4. The grpmax FAF for this variant is 9.55e-06 (0.000955%), far below the 0.5% threshold.	gnomad_v4
BS1	Not met	The ATM VCEP BS1 rule requires a grpmax filtering allele frequency >0.05% in gnomAD v4. The grpmax FAF for this variant is 9.55e-06 (0.000955%), far below the 0.05% threshold.	gnomad_v4
BS2	N/A	BS2 (observed in healthy adult with full penetrance expected) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
BS3	Met	The ATM VCEP BS3_Supporting rule applies when a variant rescues EITHER an ATM-specific feature OR radiosensitivity. Lee et al. 2025 (PMID:40580951, Cell) performed saturation prime editing of all 27,513 possible ATM SNVs and assessed cell fitness in the presence of olaparib, a PARP inhibitor that creates synthetic lethality with ATM deficiency. NM_000051.4:c.8155C>T (p.Arg2719Cys) was classified as 'Functional' with 'High' confidence, indicating the variant retains ATM activity in the DNA damage response and rescues an ATM-specific function.	PMID:40580951 vcep_suppl_tables1_pmid_40580951
BS4	N/A	BS4 (lack of segregation) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
BP1	N/A	BP1 (missense in gene where truncating cause disease) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
BP2	Not met	The ATM VCEP BP2 rule assigns points when the variant is observed in trans with a pathogenic or likely pathogenic ATM variant in an unaffected (non-A-T) individual. No such observation was identified in the available evidence. The exploratory search did not find any unaffected individuals carrying this variant in trans with a pathogenic ATM variant.
BP3	N/A	BP3 (in-frame indels in repetitive region) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
BP4	Not met	The ATM VCEP BP4 rule for missense variants requires REVEL ≤0.249. The REVEL score for this variant is 0.613, which does not meet the benign threshold. Although SpliceAI predicts no splicing impact (max delta=0.03 ≤0.1), the missense-specific REVEL rule takes precedence and is not satisfied.	revel spliceai
BP5	N/A	BP5 (variant found in case with alternate molecular basis) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
BP6	N/A	BP6 (reputable source reports variant as benign) is marked Not Applicable by the ATM VCEP v1.5.0 specifications.	cspec
BP7	Not met	The ATM VCEP BP7 rule applies to synonymous and deep intronic variants (further than +7 and -21 from donor/acceptor sites). The BP7(RNA) sub-rule can apply when RNA studies demonstrate a lack of aberrant splicing for silent or intronic variants. NM_000051.4:c.8155C>T is a missense variant, not a synonymous or deep intronic variant, and therefore does not qualify for BP7.	spliceai

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