Variant classification summary

NM_000051.4:c.1009C>T

ATM · NP_000042.3:p.(Arg337Cys) · NM_000051.4

GRCh37: chr11:108117798 C>T · GRCh38: chr11:108247071 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.(Arg337Cys)

gnomAD AF

8.923658104912473e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.1009C>T (p.Arg337Cys) is a missense variant in ATM exon 8.

2

This variant is present in gnomAD v4.1 at an overall allele frequency of 0.00892% (144/1,613,688 alleles, 0 homozygotes) with a grpmax filtering allele frequency of 0.021% in the Admixed American population.

3

This variant does not meet PM2_Supporting (frequency ≤0.001% required), BS1 (>0.05% required), or BA1 (>0.5% required) under ATM VCEP population thresholds.

4

This variant has been reported in ClinVar (Variation ID 127327) as Uncertain Significance by 18 clinical laboratories and as Likely Benign by 3 clinical laboratories; no submitter classifies it as pathogenic.

5

The variant has been reported 80 times in somatic cancers (COSMIC COSV53723836) and OncoKB classifies it as Likely Oncogenic with a loss-of-function effect in the somatic context.

6

Computational predictors do not support a deleterious effect: REVEL score is 0.36 (VCEP PP3 threshold >0.7333, BP4 threshold ≤0.249), SpliceAI max delta is 0.10, and BayesDel is 0.067.

7

The ATM VCEP functional dataset (Suppl_TableS1, PMID 40580951) classifies this variant as 'Functional' (combined score -0.65, high confidence) based on integrated functional and evolutionary scores, meeting BS3_Supporting under VCEP rules.

8

PVS1, PS1, PS2, PM1, PM5, PM6, PP2, PP4, PP5, BS2, BS4, BP1, BP5, BP6, and BP7 are not applicable under ATM VCEP v1.5.0 for this variant type.

9

No case-control study demonstrates enrichment of this variant in affected individuals (PS4 not met), and no segregation data are available (PP1 not assessed).

10

With only BS3_Supporting met and no pathogenic criteria fulfilled, the evidence is insufficient to classify this variant as either likely benign or likely pathogenic; the variant remains a Variant of Uncertain Significance under the ATM VCEP framework.

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	NM_000051.4:c.1009C>T is a missense substitution (p.Arg337Cys) and does not meet the ATM VCEP PVS1 null-variant criteria (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon deletion).	pvs1_variant_assessment
PS1	Not met	No missense variant at codon 337 (Arg337) has been classified as pathogenic or likely pathogenic by VCEP criteria. All known missense substitutions at this residue (R337S, R337G, R337P, R337L, R337H) are classified as VUS or conflicting in ClinVar. PS1 requires a previously established pathogenic missense at the same amino acid position.	clinvar vcep_suppl_tables1_pmid_40580951
PS2	N/A	ATM VCEP v1.5.0 specifies PS2 is not applicable: de novo occurrences have not been observed for this gene and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not met	The ATM VCEP functional dataset (Suppl_TableS1, PMID 40580951) classifies c.1009C>T (p.Arg337Cys) as 'Functional' with a combined score of -0.65, indicating retention of ATM activity. PS3 requires failure to rescue ATM function; this variant demonstrates functional rescue.	vcep_suppl_tables1_pmid_40580951
PS4	Not met	No case-control study demonstrates statistically significant enrichment of this variant in affected individuals. The gnomAD population frequency (0.009% overall, grpmax FAF 0.021%) and the Tavtigian et al. 2009 neutral classification argue against a strong case enrichment required for PS4_Strong under VCEP rules (OR ≥2, p≤0.05, or lower 95% CI ≥1.5).	gnomad_v4 clinvar
PS5	Not met	No pathogenic or likely pathogenic missense variant has been established at codon 337 (Arg337). All missense substitutions at this residue (R337S, R337G, R337P, R337L, R337H) are classified as VUS or conflicting classifications. Under generic ACMG/AMP rules, PS5 requires a previously established pathogenic missense at the same residue.	clinvar vcep_suppl_tables1_pmid_40580951
PM1	N/A	ATM VCEP v1.5.0 specifies PM1 is not applicable: benign and pathogenic variants are known to occur within the same domains, and germline mutational hotspots are not well defined.	cspec
PM2	Not met	gnomAD v4.1 allele frequency is 0.00892% (144/1,613,688 alleles), exceeding the ATM VCEP PM2_Supporting threshold of ≤0.001%. The variant is not sufficiently rare to meet PM2.	gnomad_v4
PM5	N/A	ATM VCEP PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or splice variants with PVS1_RNA. This is a missense substitution and is explicitly excluded (VCEP: 'Do not use for missense changes').	cspec pm5_candidates
PM6	N/A	ATM VCEP v1.5.0 specifies PM6 is not applicable: informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not assessed	No published cosegregation data are available for this variant in families with ATM-related conditions. The VCEP PP1 applies only to AR conditions with affected relatives sharing both variants; no such data have been identified.
PP2	N/A	ATM VCEP v1.5.0 specifies PP2 is not applicable: ATM does not have a defined low rate of benign missense variation.	cspec
PP3	Not met	REVEL score 0.36 does not meet the ATM VCEP PP3 threshold (>0.7333) for missense variants. SpliceAI max delta score 0.10 does not meet the splicing threshold (≥0.2). Multiple lines of computational evidence do not support a deleterious effect.	revel bayesdel spliceai
PP4	N/A	ATM VCEP v1.5.0 specifies PP4 is not applicable: breast cancer has multiple genetic etiologies and no features distinguish hereditary from sporadic causes.	cspec
PP5	N/A	PP5 is not for use under ATM VCEP v1.5.0 as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	gnomAD v4.1 grpmax filtering allele frequency is 0.021% (2.07×10⁻⁴), well below the ATM VCEP BA1 threshold of >0.5%.	gnomad_v4
BS1	Not met	gnomAD v4.1 grpmax filtering allele frequency is 0.021% (2.07×10⁻⁴), below the ATM VCEP BS1 threshold of >0.05%.	gnomad_v4
BS2	N/A	ATM VCEP v1.5.0 specifies BS2 is not applicable: ATM has incomplete penetrance.	cspec
BS3	Met	The ATM VCEP functional dataset (Suppl_TableS1, PMID 40580951) classifies c.1009C>T (p.Arg337Cys) as 'Functional' (combined score -0.65, function score 31, high confidence), indicating retention of ATM activity. Under VCEP BS3 rules, a variant that rescues ATM-specific functional features (e.g., kinase activity) meets BS3_Supporting. Functional studies in the Barone et al. 2009 and Mitui et al. 2009 datasets demonstrate retained ATM kinase activity for this variant.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	ATM VCEP v1.5.0 specifies BS4 is not applicable: informative instances of lack of co-segregation in A-T families are too rare, and co-segregation analysis in low-penetrance genes can produce false positives.	cspec
BP1	N/A	ATM VCEP v1.5.0 specifies BP1 is not applicable: missense pathogenic variants are known for ATM.	cspec
BP2	Not met	No confirmed observation of this variant in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual aged ≥18 years has been verified. gnomAD reports zero homozygotes across v2.1 and v4.1, providing no support for BP2 via homozygosity. A subagent report of in-trans co-occurrence with c.7271T>G (Kanavy 2020) could not be confirmed from available full-text sources.	gnomad_v4 gnomad_v2
BP4	Not met	REVEL score 0.36 exceeds the ATM VCEP BP4 threshold (≤0.249) for missense variants. SpliceAI max delta is 0.10, which meets the splicing BP4 threshold (≤0.1), but the missense-specific rule takes precedence and is not satisfied.	revel spliceai bayesdel
BP5	N/A	ATM VCEP v1.5.0 specifies BP5 is not applicable: cases with multiple pathogenic variants are observed without noticeable phenotype difference, and ATM has low penetrance with higher tolerance in the general population.	cspec
BP6	N/A	BP6 is not for use under ATM VCEP v1.5.0 as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 under ATM VCEP v1.5.0 applies only to synonymous and deep intronic variants (further than +7 donor / -21 acceptor). This is a missense substitution (c.1009C>T, p.Arg337Cys) and does not qualify.	cspec

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