NM_000051.4:c.5488A>G

ATM · NP_000042.3:p.(Met1830Val) · NM_000051.4

GRCh37: chr11:108173748 A>G · GRCh38: chr11:108303021 A>G

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

BS3 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Met1830Val)

gnomAD AF

1.675314183458072e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000051.4:c.5488A>G (p.Met1830Val) is a missense variant in ATM, a gene in which loss of function is an established mechanism for ataxia telangiectasia (autosomal recessive) and where pathogenic variants confer moderate-risk susceptibility to hereditary breast, ovarian, and pancreatic cancer (autosomal dominant).

This variant is observed in gnomAD v4.1 at an overall allele frequency of 0.001675% (27/1,611,638 alleles; grpmax FAF = 0.0226%), which is rare but above the VCEP PM2 threshold of 0.001%, and does not meet BA1 (>0.5%), BS1 (>0.05%), or PM2_Supporting (≤0.001%) population thresholds.

VCEP-endorsed functional data (Table S1, PMID:40580951) classifies M1830V as 'Functional' with 'High' confidence (Combined_score = -0.63; DeepATM predicted not pathogenic), indicating the variant retains ATM function. This supports BS3_Supporting per VCEP rules.

Computational predictors consistently suggest a benign impact: REVEL = 0.146 (BP4 threshold ≤0.249), BayesDel = -0.31326, AlphaMissense = 0.0733, and SpliceAI max delta = 0.04. This supports BP4_Supporting per VCEP rules.

This variant has been reported in ClinVar as Uncertain significance by 7 clinical laboratories and Likely benign by 4 clinical laboratories (ClinVar Variation ID: 141271). It has been observed as a somatic variant (M1830V, VUS) in a metastatic pancreatic cancer case (PMID:27034805), but this somatic observation does not inform germline classification.

Applying the VCEP HBOP ATM v1.5.0 framework: met criteria include BS3_Supporting and BP4_Supporting (2 benign supporting criteria). No pathogenic criteria are met. Per ACMG/AMP combination rules (Rule 19), ≥2 benign supporting criteria support a classification of Likely Benign.

Final determination: Rule19 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

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	Missense substitution (p.Met1830Val) is not a null variant. The ATM VCEP PVS1 decision tree applies only to nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion variants.	vcep_atm_pvs1_1_5 pvs1_generic_framework
PS1	Not met	No same-amino-acid change at residue 1830 has been established as pathogenic by the ATM VCEP. The VCEP PS1 splicing table applies only to splicing variants, not missense substitutions. SpliceAI delta = 0.04 rules out cryptic splicing concern.	vcep_atm_ps1_1_5 spliceai
PS2	N/A	ATM VCEP specifies PS2 is not applicable: informative de novo occurrences have not been observed for ATM and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not met	VCEP-endorsed functional data (Table S1, PMID:40580951) classifies M1830V as 'Functional' with 'High' confidence and Combined_score = -0.63, indicating retained ATM function. DeepATM predicts 'No' (not pathogenic). No evidence of damaging effect on protein function.	vcep_suppl_tables1_pmid_40580951 cspec
PS4	Not assessed	No case-control study data available for this variant. VCEP PS4 requires case-control studies with p≤0.05 and OR≥2 or lower 95% CI ≥1.5. No such evidence was identified.	cspec
PS5	N/A	PS5 is not included in the ATM VCEP criteria set (HBOP VCEP v1.5.0). This criterion is not part of the VCEP framework for ATM variant classification.	cspec
PM1	N/A	ATM VCEP specifies PM1 is not applicable: benign and pathogenic variants occur within the same ATM domains and germline mutational hotspots are not well defined.	cspec
PM2	Not met	gnomAD v4.1 allele frequency = 27/1,611,638 (AF = 0.001675%), which exceeds the VCEP PM2_Supporting threshold of ≤0.001%. The variant is present in 27 alleles across population databases, including 4 alleles in the Middle Eastern subpopulation (AF=0.066%).	gnomad_v4 cspec
PM5	N/A	VCEP PM5 applies only to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with NMD-prone PTCs. Missense changes are explicitly excluded: 'Do not use for missense changes.'	cspec pm5_candidates
PM6	N/A	ATM VCEP specifies PM6 is not applicable: informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not assessed	No segregation data available. VCEP PP1 applies only to AR condition (ataxia telangiectasia) and requires affected relatives with both variants identified. No AT family segregation data were identified for this variant.	cspec
PP2	N/A	ATM VCEP specifies PP2 is not applicable: ATM does not have a defined low rate of benign missense variation.	cspec
PP3	Not met	REVEL score = 0.146, which is well below the VCEP PP3 threshold of >0.7333 for missense variants. SpliceAI max delta = 0.04, indicating no predicted splicing impact. Multiple in silico tools do not support a deleterious effect.	revel bayesdel spliceai cspec
PP4	N/A	ATM VCEP specifies PP4 is not applicable: breast cancer has multiple genetic etiologies (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. For AR disease, such evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	ATM VCEP specifies PP5 is not applicable: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	gnomAD v4.1 grpmax Filtering AF = 0.00022553 (0.0226%), which is far below the VCEP BA1 threshold of >0.5% (grpmax FAF). The variant is not common enough to qualify as a stand-alone benign polymorphism.	gnomad_v4 cspec
BS1	Not met	gnomAD v4.1 grpmax Filtering AF = 0.00022553 (0.0226%), which is below the VCEP BS1 threshold of >0.05%. The variant is not sufficiently frequent in population databases to support a benign interpretation under BS1.	gnomad_v4 cspec
BS2	N/A	ATM VCEP specifies BS2 is not applicable: ATM has incomplete penetrance, so observation in a healthy adult does not provide sufficient evidence for benign classification.	cspec
BS3	Met	VCEP-endorsed functional assay data (Table S1, PMID:40580951) classifies M1830V as 'Functional' with 'High' confidence (Combined_score = -0.63; DeepATM_predicted = 'No'), indicating the variant rescues ATM function. Per VCEP BS3 rules, rescue of an ATM-specific feature qualifies for BS3_Supporting.	vcep_suppl_tables1_pmid_40580951 cspec
BS4	N/A	ATM VCEP specifies BS4 is not applicable: lack of segregation analysis in low-penetrance genes can produce false positives (AD), and informative instances of lack of co-segregation in A-T families are too rare for weighting (AR).	cspec
BP1	N/A	ATM VCEP specifies BP1 is not applicable: missense pathogenic variants are known for ATM, so a missense variant cannot be presumed benign solely because truncating variants are the primary disease mechanism.	cspec
BP2	Not assessed	No AT proband data with biallelic co-occurrence in unaffected individuals available. VCEP BP2 requires scoring per the ATM PM3/BP2 table based on unaffected individuals (≥18 years, no A-T) with the variant in trans or homozygous with a P/LP variant.	cspec vcep_atm_pm3_bp2_1_5
BP4	Met	REVEL score = 0.146, which is ≤0.249 meeting the VCEP BP4 threshold for missense variants. SpliceAI max delta = 0.04 ≤ 0.1, indicating no predicted splicing impact. BayesDel = -0.31326. Multiple computational tools consistently predict a benign impact.	revel bayesdel spliceai cspec
BP5	N/A	ATM VCEP specifies BP5 is not applicable: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance with higher tolerance for co-occurring variants in the general population.	cspec
BP6	N/A	ATM VCEP specifies BP6 is not applicable: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	VCEP BP7 applies to synonymous and deep intronic variants (beyond +7 donor and -21 acceptor). This is a missense substitution (c.5488A>G, p.Met1830Val) and does not fall within the BP7 variant scope.	cspec
BP3	N/A	In-frame deletions/insertions in repetitive regions; not applicable to single-nucleotide missense substitutions.
PM3	N/A	Recessive disorder trans-configuration evidence requires AT proband data; no AT proband co-occurrence data reviewed for this variant.
PM4	N/A	VCEP PM4 applies only to stop-loss variants; missense substitution does not alter protein length.

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