Variant classification summary

NM_000051.4:c.6200C>A

ATM · NP_000042.3:p.(Ala2067Asp) · NM_000051.4

GRCh37: chr11:108188101 C>A · GRCh38: chr11:108317374 C>A

Gene: ATM Transcript: NM_000051.4

Final call

Likely Pathogenic

PM3 strong PM2 supporting PS3 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Ala2067Asp)

gnomAD AF

3.1045179428719024e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.6200C>A (p.Ala2067Asp; p.A2067D) variant has been reported in ClinVar with multiple pathogenic and likely pathogenic germline submissions, and variant-specific cancer curation has linked it to literature consistent with loss of ATM function.

2

This variant is very rare in population databases, with gnomAD v4.1 showing an allele frequency of 3.10452e-06 (5/1610556 alleles), no homozygotes, and grpmax filtering allele frequency 8e-07, which supports rarity for ATM.

3

In a published functional study, patient-derived and engineered cells showed markedly reduced ATM protein, absent ATM Ser1981 autophosphorylation, and trace-to-absent phosphorylation of downstream ATM targets, supporting a damaging effect on ATM function.

4

Computational evidence does not meet the ATM PP3 or BP4 missense thresholds: REVEL is 0.435, BayesDel is 0.0616905, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01.

Final determination: Rule12 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 Pathogenic.

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
BP3	N/A	BP3 is not used for ATM under the ClinGen HBOP ATM specifications.	cspec
BP2	Not assessed	No unaffected adult individual with this variant observed in trans with a pathogenic or likely pathogenic ATM variant, and no qualifying benign co-occurrence evidence was identified.	cspec vcep_atm_pm3_bp2_1_5
BA1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 8e-07, which is far below the ATM BA1 threshold of greater than 0.5%.	gnomad_v4 cspec
PP4	N/A	PP4 is not used for ATM under this specification because the relevant recessive phenotype evidence is incorporated into the ATM PM3/BP2 framework and the dominant phenotype is genetically heterogeneous.	cspec
PM6	N/A	PM6 is not used for ATM under the ClinGen HBOP ATM specifications.	cspec
PS4	Not assessed	Published case reports and series were identified, but no qualifying variant-specific case-control result with p-value 0.05 or less and odds ratio, hazard ratio, or relative risk of at least 2, or lower 95% confidence interval of at least 1.5, was confirmed from the available evidence.	cspec PMID:20305132 PMID:26898890
BP6	N/A	BP6 is not for use in this VCEP framework.	cspec
PM5	N/A	For ATM, PM5 is restricted to truncating or qualifying splice variants upstream of p.Arg3047 and is not used for missense changes. This variant is missense.	cspec pm5_candidates
PM1	N/A	PM1 is not used for ATM because germline mutational hotspots are not well defined and both benign and pathogenic variants occur within the same domains.	cspec
PS2	N/A	PS2 is not used for ATM under the ClinGen HBOP ATM specifications.	cspec
PS1	Not met	No previously established pathogenic ATM variant producing the same amino acid substitution was identified from the available evidence, so PS1 is not met.	cspec vcep_atm_ps1_1_5 clinvar
BP5	N/A	BP5 is not used for ATM under this specification.	cspec
PP3	Not met	For this missense variant, the REVEL score is 0.435, which is below the ATM PP3 threshold of greater than 0.7333. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, which is below the splice-impact threshold of 0.2. These results do not support PP3.	cspec revel spliceai
PP2	N/A	PP2 is not used for ATM under the ClinGen HBOP ATM specifications.	cspec
PM3	Met	This variant has been reported in multiple affected individuals with variant ataxia-telangiectasia, including homozygous affected members in Canadian Mennonite families. Under the ATM PM3 framework, homozygous affected individuals can contribute points up to the cap of two individuals; this supports PM3 at strong strength.	cspec vcep_atm_pm3_bp2_1_5 PMID:25077176
PM2	Met	This variant is very rare in gnomAD v4.1, with a total allele frequency of 3.10452e-06 (0.00031%), 5 of 1610556 alleles observed, no homozygotes, and grpmax filtering allele frequency 8e-07. This is below the ATM PM2 threshold of 0.001%, supporting PM2 at supporting strength.	gnomad_v4 cspec
PVS1	N/A	This is a missense variant and does not fall into the ATM or generic PVS1 null-variant categories such as nonsense, frameshift, canonical splice-site, initiation codon, or exon-level loss-of-function events.	cspec pvs1_gene_context pvs1_variant_assessment vcep_atm_pvs1_1_5
BP7	N/A	BP7 is intended for synonymous or deep intronic variants, not for this missense variant.	cspec
BS1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 8e-07, which is well below the ATM BS1 threshold of greater than 0.05%.	gnomad_v4 cspec
PM4	N/A	PM4 is used for ATM stop-loss variants only, and this variant is missense.	cspec
BP4	Not met	The REVEL score is 0.435, which is above the ATM BP4 missense threshold of 0.249 or less, so missense computational evidence does not support BP4. SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, but this does not overcome the non-benign missense prediction under the ATM missense BP4 rule.	cspec revel spliceai bayesdel
BP1	N/A	BP1 is not used for ATM under the ClinGen HBOP ATM specifications.	cspec
BS4	N/A	BS4 is not used for ATM under the ClinGen HBOP ATM specifications.	cspec
BS3	Not met	Available functional evidence does not show rescue of ATM function. In a published functional study, patient-derived and engineered cells showed markedly reduced ATM protein with absent ATM autophosphorylation and trace-to-absent phosphorylation of downstream ATM targets, which argues against BS3.	cspec PMID:25077176
BS2	N/A	BS2 is not used for ATM under the ClinGen HBOP ATM specifications.	cspec
PP5	N/A	PP5 is not used in this VCEP framework.	cspec
PP1	Not assessed	Affected family members with this variant were reported, but the available evidence does not provide sufficiently clear segregation counting under the ATM autosomal recessive PP1 framework to assign a PP1 strength level independently of PM3.	cspec
PS3	Met	In a published functional study, lymphoblastoid cells from affected individuals expressed only small amounts of ATM protein, showed no ATM Ser1981 autophosphorylation, and had trace-to-absent phosphorylation of downstream ATM targets; engineered cells expressing the variant also showed trace-to-absent downstream signaling. This demonstrates failure of an ATM-specific functional feature and supports PS3 at supporting strength.	cspec PMID:25077176

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