Variant classification summary

NM_000051.3:c.2413C>T

ATM · NP_000042.3:p.(Arg805Ter) · NM_000051.3

GRCh37: chr11:108129749 C>T · GRCh38: chr11:108259022 C>T

Gene: ATM Transcript: NM_000051.3

Final call

Pathogenic

PVS1 very strong PM5 supporting PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Arg805Ter)

gnomAD AF

8.056080233601539e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.2413C>T (p.Arg805Ter; p.R805*) variant has been reported in ClinVar as Pathogenic by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel and is also cataloged in a cancer knowledgebase with variant-specific somatic context.

2

This variant is present in gnomAD v4.1 at an overall allele frequency of 0.00081% (13/1613688) with a highest observed East Asian frequency of 0.00669% (3/44820); these values are below the ATM BS1 and BA1 thresholds but the East Asian frequency is above the ATM PM2_Supporting threshold of 0.001%.

3

Curated literature resources identify this variant in an ATM loss-of-function context, but no ATM-specific functional rescue data were confirmed here that meet the expert-panel requirements for PS3 or BS3.

4

This variant introduces a premature termination codon at Arg805, well upstream of the ATM truncation cutoff used by the expert panel, which supports PVS1 and PM5_Supporting under the ATM-specific rules; REVEL was unavailable, BayesDel was 0.588046, and no SpliceAI-based evidence was captured for a splice-specific computational call.

Final determination: Rule4 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 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
PVS1	Met	This nonsense variant introduces a premature stop codon at p.Arg805Ter (p.R805*), well upstream of the 3' end of ATM, and ATM loss of function is an established disease mechanism in the ATM HBOP expert-panel framework. Available ATM-specific PVS1 guidance therefore supports full-strength PVS1 for this early truncating variant.	cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This variant is a nonsense change and no same-effect splice comparator evidence was identified. The ATM PS1 specification is directed to missense substitutions or splice variants with matched predicted or observed splice effects, so PS1 is not applicable here.	cspec vcep_atm_ps1_1_5
PS2	N/A	The ATM HBOP specification lists PS2 as not applicable for this gene-disease framework.	cspec
PS3	Not assessed	Curated literature resources identified functional publications relevant to ATM loss of function, but no assay result was confirmed here showing that this exact variant failed to rescue both an ATM-specific feature and radiosensitivity, as required for ATM PS3. Available evidence is therefore insufficient to apply PS3.	oncokb PMID:27413114 PMID:30348496 PMID:30553448 cspec
PS4	Not met	This variant has been reported in affected individuals and is classified as Pathogenic in ClinVar, but no case-control study or other enrichment analysis meeting the ATM PS4 requirement of p-value 0.05 or less with an effect estimate of at least 2 was identified. Available evidence does not support PS4.	clinvar PMID:12815592 PMID:15843990 PMID:16941484 PMID:17910737 PMID:19691550 cspec
PM1	N/A	The ATM HBOP specification lists PM1 as not applicable for this gene-disease framework.	cspec
PM2	Not met	This variant is rare overall in gnomAD v4.1 at 13/1613688 alleles (0.00081%), but the highest observed subpopulation frequency is 3/44820 East Asian alleles (0.00669%), which is above the ATM PM2_Supporting threshold of 0.001%. Available population data therefore do not support PM2.	gnomad_v4 cspec
PM3	Not assessed	No proband-level phase data were identified showing this variant in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia. Available evidence is insufficient to assign PM3 points.	vcep_atm_pm3_bp2_1_5 cspec
PM4	N/A	This is not a stop-loss variant. The ATM HBOP framework reserves PM4 for stop-loss variants, so PM4 is not applicable.	cspec
PM5	Met	The ATM HBOP specification permits PM5 at supporting strength for truncating variants with premature termination codons upstream of p.Arg3047. This variant creates p.Arg805Ter, which is far upstream of p.Arg3047, so PM5_Supporting is met under the ATM-specific rule.	cspec pm5_candidates
PM6	N/A	The ATM HBOP specification lists PM6 as not applicable for this gene-disease framework.	cspec
PP1	Not assessed	No segregation data were identified showing this variant tracking with disease in affected relatives. Available evidence is insufficient to apply PP1.	PMID:12815592 PMID:17910737 PMID:19691550 cspec
PP2	N/A	The ATM HBOP specification lists PP2 as not applicable for this gene-disease framework.	cspec
PP3	N/A	ATM PP3 is specified for missense variants with REVEL greater than 0.7333 or for non-canonical splice-relevant variants with SpliceAI 0.2 or higher. This variant is a nonsense change, REVEL was not available, no SpliceAI-based splice evidence was captured, and the observed BayesDel score of 0.588046 does not create an ATM-specific PP3 pathway for a truncating variant, so PP3 is not applicable.	cspec bayesdel spliceai
PP4	N/A	The ATM HBOP specification lists PP4 as not applicable for this gene-disease framework.	cspec
PP5	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	The highest gnomAD v4.1 filtering allele frequency is 0.001775%, which is below the ATM BA1 threshold of greater than 0.5%. Population data do not support BA1.	gnomad_v4 cspec
BS1	Not met	The highest gnomAD v4.1 filtering allele frequency is 0.001775%, which is below the ATM BS1 threshold of greater than 0.05%. Population data do not support BS1.	gnomad_v4 cspec
BS2	N/A	The ATM HBOP specification lists BS2 as not applicable for this gene-disease framework.	cspec
BS3	Not assessed	Curated literature resources identified functional publications relevant to ATM, but no confirmed assay result was identified here showing rescue of both an ATM-specific feature and radiosensitivity, or rescue of either feature alone, as required for ATM BS3. Available evidence is insufficient to apply BS3.	oncokb PMID:27413114 PMID:30348496 PMID:30553448 cspec
BS4	N/A	The ATM HBOP specification lists BS4 as not applicable for this gene-disease framework.	cspec
BP1	N/A	The ATM HBOP specification lists BP1 as not applicable for this gene-disease framework.	cspec
BP2	Not assessed	No confirmed co-occurrence data were identified showing this variant in trans with a pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual, or in another qualifying benign co-occurrence setting. Available evidence is insufficient to assign BP2 points.	vcep_atm_pm3_bp2_1_5 cspec
BP3	N/A	The ATM HBOP specification lists BP3 as not applicable for this gene-disease framework.	cspec
BP4	N/A	ATM BP4 is specified for missense variants with REVEL 0.249 or lower or for non-canonical splice-relevant variants with SpliceAI 0.1 or lower. This variant is a nonsense change, REVEL was not available, no SpliceAI-based splice evidence was captured, and the observed BayesDel score of 0.588046 does not create an ATM-specific BP4 pathway for a truncating variant, so BP4 is not applicable.	cspec bayesdel spliceai
BP5	N/A	The ATM HBOP specification lists BP5 as not applicable for this gene-disease framework.	cspec
BP6	N/A	The ATM HBOP specification lists BP6 as not applicable for this gene-disease framework.	cspec
BP7	N/A	This variant is not synonymous or deep intronic, and the ATM BP7 specification is intended for synonymous and defined intronic variants or RNA evidence showing no splice defect. BP7 is not applicable.	cspec

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