Variant classification summary

NM_000051.3:c.5681_5682del

ATM · NP_000042.3:p.(Glu1894AlafsTer9) · NM_000051.3

GRCh37: chr11:108178627 CAG>C · GRCh38: chr11:108307900 CAG>C

Gene: ATM Transcript: NM_000051.3

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting PP5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Glu1894AlafsTer9)

gnomAD AF

1.8599391427912479e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM NM_000051.3:c.5681_5682del (NP_000042.3:p.(Glu1894AlafsTer9); p.(E1894Afs*9)) variant has been reported in ClinVar and is classified there as pathogenic, including by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and is present only 3 times in gnomAD v4.1 (AF 1.85994e-06; 0 homozygotes), which is below the ATM PM2_Supporting threshold of 0.001% and well below the BS1 and BA1 thresholds.

3

The variant is a frameshift predicted to truncate ATM at codon 1894, and under the ATM VCEP framework this supports PVS1 because loss of function is an established disease mechanism for ATM; the ATM-specific PM5 truncation rule also applies because the premature termination is upstream of p.Arg3047.

4

SpliceAI predicts no significant splice effect for this variant (maximum delta score 0.14), which is below the ATM PP3 splice threshold of 0.2 and above the BP4 benign splice threshold of 0.1.

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 variant is a frameshift, NM_000051.3:c.5681_5682del, predicted to cause p.(Glu1894AlafsTer9) [p.(E1894Afs*9)]. The ATM VCEP includes gene-specific PVS1 guidance, loss of function is an established disease mechanism for ATM, and this truncating change is not at the extreme 3′ end, supporting PVS1 at very strong strength.	cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This variant is a frameshift deletion and not a missense change or qualifying splice comparator under the ATM PS1 framework, so PS1 does not apply.	cspec vcep_atm_ps1_1_5
PS2	N/A	PS2 is marked not applicable in the ATM VCEP specifications used for this review.	cspec
PS3	Not assessed	No variant-specific functional study was identified that showed this exact variant failed to rescue an ATM-specific feature or failed to rescue both an ATM-specific feature and radiosensitivity, which is required by the ATM VCEP framework for PS3.	cspec oncokb PMID:27413114 PMID:30348496 PMID:30553448
PS4	Not assessed	ClinVar reports this variant in germline disease databases, but no case-control study or quantified enrichment data meeting the ATM VCEP PS4 threshold were identified.	cspec clinvar PMID:23807571 PMID:25614872 PMID:26896183
PM1	N/A	PM1 is marked not applicable in the ATM VCEP specifications used for this review.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and is present only 3 times in gnomAD v4.1 (AF 1.85994e-06, 0.00019%; highest observed population AF 1.60149e-05, 0.00160%; 0 homozygotes), which is below the ATM VCEP PM2_Supporting threshold of 0.001%.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Published and database observations suggest this variant has been seen in individuals with ataxia-telangiectasia, but the retrieved evidence did not establish confirmed in trans occurrence with a pathogenic ATM variant, phase-unknown point totals, or qualifying homozygous evidence needed to score PM3 under the ATM point-based framework.	cspec vcep_atm_pm3_bp2_1_5 clinvar PMID:23807571 PMID:25614872 PMID:26896183
PM4	N/A	The ATM VCEP reserves PM4 for stop-loss variants. This variant is a frameshift deletion, so PM4 does not apply.	cspec
PM5	Met	Under the ATM VCEP framework, PM5_Supporting applies to truncating variants with premature termination codons upstream of p.Arg3047. This frameshift produces p.(Glu1894AlafsTer9), which is upstream of p.Arg3047, so PM5 is met at supporting strength.	cspec pm5_candidates
PM6	N/A	PM6 is marked not applicable in the ATM VCEP specifications used for this review.	cspec
PP1	Not assessed	No segregation data were identified showing this variant tracking with ataxia-telangiectasia in affected relatives, so PP1 could not be applied.	cspec
PP2	N/A	PP2 is marked not applicable in the ATM VCEP specifications used for this review.	cspec
PP3	Not met	For ATM, PP3 for splicing requires SpliceAI at least 0.2. This variant has a maximum SpliceAI delta score of 0.14, which is below that threshold, and REVEL/BayesDel are not applicable to this deletion.	cspec spliceai
PP4	N/A	PP4 is marked not applicable in the ATM VCEP specifications used for this review.	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 observed gnomAD v4 filtering allele frequency for this variant is 2.8e-07, which is far below the ATM BA1 threshold of greater than 0.5%, so BA1 is not met.	cspec gnomad_v4
BS1	Not met	The highest observed gnomAD v4 filtering allele frequency for this variant is 2.8e-07, which is below the ATM BS1 threshold of greater than 0.05%, so BS1 is not met.	cspec gnomad_v4
BS2	N/A	BS2 is marked not applicable in the ATM VCEP specifications used for this review.	cspec
BS3	Not assessed	No variant-specific functional study was identified showing this exact variant rescued an ATM-specific feature or radiosensitivity, which is required by the ATM VCEP framework for BS3.	cspec oncokb PMID:27413114 PMID:30348496 PMID:30553448
BS4	N/A	BS4 is marked not applicable in the ATM VCEP specifications used for this review.	cspec
BP1	N/A	BP1 is marked not applicable in the ATM VCEP specifications used for this review.	cspec
BP2	Not assessed	No qualifying evidence was identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual, so BP2 could not be applied.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	BP3 is marked not applicable in the ATM VCEP specifications used for this review.	cspec
BP4	Not met	For ATM, BP4 for splicing requires SpliceAI 0.1 or lower. This variant has a maximum SpliceAI delta score of 0.14, which is above that benign threshold, and REVEL-based missense assessment is not applicable to this deletion.	cspec spliceai
BP5	N/A	BP5 is marked not applicable in the ATM VCEP specifications used for this review.	cspec
BP6	N/A	BP6 is marked not applicable in the ATM VCEP specifications used for this review.	cspec
BP7	N/A	BP7 is intended for synonymous or qualifying deep intronic variants, or RNA studies showing no aberrant splicing. This variant is a frameshift deletion, so BP7 does not apply.	cspec

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