Variant classification summary

NM_000051.3:c.3118A>G

ATM · NP_000042.3:p.(Met1040Val) · NM_000051.3

GRCh37: chr11:108143299 A>G · GRCh38: chr11:108272572 A>G

Gene: ATM Transcript: NM_000051.3

Final call

Benign

BA1 stand-alone benign BS1 strong BP4 supporting BP6 supporting benign

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Met1040Val)

gnomAD AF

0.002096934905786648 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.3118A>G (p.Met1040Val) variant has been observed in somatic cancers 4 times in COSMIC and is reported in ClinVar as Benign with expert panel review.

2

This variant is common in population databases, with gnomAD v4.1 showing an overall allele frequency of 0.20969% and an African/African American allele frequency of 3.97073%, which exceeds the ATM BA1 threshold of 0.5% grpmax filtering allele frequency.

3

Computational evidence supports a benign effect, with REVEL 0.096, BayesDel -0.451498, and SpliceAI maximum delta score 0.01, meeting the ATM BP4 thresholds and not meeting PP3 thresholds.

Final determination: Rule17 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 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	This is a missense variant, and available evidence does not indicate a null effect or canonical splice-site disruption; therefore the ATM PVS1 rule does not apply.	cspec pvs1_gene_context pvs1_variant_assessment vcep_atm_pvs1_1_5 spliceai
PS1	Not assessed	No established pathogenic or likely pathogenic comparator producing the same amino acid change or the same predicted splice event was identified, so PS1 was not assessed.	cspec vcep_atm_ps1_1_5 spliceai
PS2	N/A	The ATM CSPEC marks PS2 as not applicable in this framework.	cspec
PS3	Not assessed	No validated ATM functional study for this exact variant was identified showing failure to rescue an ATM-specific feature or radiosensitivity in a manner that meets the ATM PS3 framework.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not met	This variant has been reported in ClinVar and 4 times in COSMIC, but no case-control study showing p-value ≤0.05 with odds ratio, hazard ratio, or relative risk ≥2 was identified. Its population frequency in gnomAD v4.1 is 0.20969% overall and 3.97073% in the African/African American population, which does not support enrichment in affected individuals.	cspec clinvar gnomad_v4
PM1	N/A	The ATM CSPEC marks PM1 as not applicable in this framework.	cspec
PM2	Not met	Population frequency is above the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4.1. The observed overall AF is 0.20969% and the highest population AF is 3.97073% in African/African American individuals.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	No confirmed observation of this variant in trans with a pathogenic or likely pathogenic ATM variant in an individual with ataxia-telangiectasia was identified.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	This is not a stop-loss variant, so PM4 does not apply.	cspec
PM5	N/A	In the ATM CSPEC, PM5 is not classic same-residue missense logic for this variant type. The reviewed PM5 candidate file indicates that PM5 is a truncation-cutoff or non-missense rule here, so it does not apply to this missense change.	cspec pm5_candidates
PM6	N/A	The ATM CSPEC marks PM6 as not applicable in this framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	cspec
PP2	N/A	The ATM CSPEC marks PP2 as not applicable in this framework.	cspec
PP3	Not met	Computational evidence does not meet the ATM PP3 threshold. REVEL is 0.096, which is below the missense PP3 cutoff of >0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, below the splice PP3 cutoff of ≥0.2.	cspec revel spliceai bayesdel
PP4	N/A	The ATM CSPEC marks PP4 as not applicable in this framework.	cspec
PP5	N/A	The ATM CSPEC marks PP5 as not applicable in this framework.	cspec
BA1	Met	This variant exceeds the ATM BA1 threshold of >0.5% grpmax filtering allele frequency in gnomAD v4.1. The highest observed population frequency is 3.97073% in African/African American individuals, with grpmax FAF 3.85176%.	cspec gnomad_v4 gnomad_v2
BS1	Met	This variant exceeds the ATM BS1 threshold of >0.05% grpmax filtering allele frequency in gnomAD v4.1. The highest observed population frequency is 3.97073% in African/African American individuals, which is far above this threshold.	cspec gnomad_v4 gnomad_v2
BS2	N/A	The ATM CSPEC marks BS2 as not applicable in this framework.	cspec
BS3	Not assessed	No validated ATM functional study for this exact variant was identified showing rescue of an ATM-specific feature and/or radiosensitivity in a manner that meets the ATM BS3 framework.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	The ATM CSPEC marks BS4 as not applicable in this framework.	cspec
BP1	N/A	The ATM CSPEC marks BP1 as not applicable in this framework.	cspec
BP2	Not assessed	No confirmed cis or trans co-occurrence data with a pathogenic or likely pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual were identified, so BP2 was not assessed.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	The ATM CSPEC marks BP3 as not applicable in this framework.	cspec
BP4	Met	Computational evidence supports a benign effect. REVEL is 0.096, below the ATM BP4 missense threshold of ≤0.249, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, below the BP4 splice threshold of ≤0.1. BayesDel is also negative at -0.451498, which is concordant with a benign computational profile.	cspec revel spliceai bayesdel
BP5	N/A	The ATM CSPEC marks BP5 as not applicable in this framework.	cspec
BP6	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	N/A	This is a missense variant rather than a synonymous or deep intronic change, so BP7 does not apply.	cspec spliceai

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