Variant classification summary

NM_000051.4:c.7875_7876delinsGC

ATM · NP_000042.3:p.(Asp2625_Ala2626delinsGluPro) · NM_000051.4

GRCh37: chr11:108203575 TG>GC · GRCh38: chr11:108332848 TG>GC

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PS3 supporting PM2 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Asp2625_Ala2626delinsGluPro)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.7875_7876delinsGC (p.Asp2625_Ala2626delinsGluPro) is an in-frame deletion-insertion in exon 55 of ATM. PVS1 does not apply as this is not a null variant type per ATM VCEP definition.

2

Functional studies demonstrate that this variant abrogates ATM kinase activity. In a genotype-phenotype study of 51 A-T patients (PMID:22213089), homozygous individuals showed ATM protein present but without detectable kinase activity (Group 2), failing to phosphorylate ATM-specific downstream targets including SMC1, KAP-1, and CREB. A separate study (PMID:10873394) found no detectable ATM protein by Western blot in a homozygous patient (AT152LA). Per ATM VCEP, PS3_Supporting applies: variant fails to rescue an ATM-specific feature (phosphorylation of targets).

3

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the ATM VCEP PM2_Supporting threshold (frequency ≤0.001%).

4

This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and Likely Pathogenic (4 laboratories) (ClinVar Variation ID: 3030). While many submitters cite supporting literature, the ClinVar classification is not independently weighted under VCEP criteria.

5

No benign criteria were met. The available evidence yields PS3_Supporting and PM2_Supporting, totaling two pathogenic supporting criteria.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.5.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	Not met	This variant is an in-frame deletion-insertion (c.7875_7876delinsGC, p.Asp2625_Ala2626delinsGluPro) and does not meet the ATM VCEP PVS1 definition of a null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion). PVS1 is reserved for variants predicted to result in absent protein via NMD or truncation.
PS1	N/A	ATM VCEP PS1 applies to missense single-nucleotide substitutions (where splicing is ruled out for both alterations) or to splicing variants via the ATM PS1 splicing table. This variant is an in-frame deletion-insertion, not a missense SNV or a splicing variant.
PS2	N/A	Marked Not Applicable by ATM VCEP v1.5.0.
PS3	Met	Functional studies demonstrate that this variant abrogates ATM kinase activity, an ATM-specific feature. In a genotype-phenotype study of 51 A-T patients (PMID:22213089), nine patients (13 alleles) carried c.7875_7876delTGinsGC; those homozygous were classified as Group 2 (ATM protein present but without detectable kinase activity), as shown by absent phosphorylation of ATM-specific downstream targets (SMC1, KAP-1, CREB). In a separate study (PMID:10873394), a homozygous patient (AT152LA) had no detectable ATM protein by Western blot. Per VCEP PS3_Supporting: variant fails to rescue an ATM-specific feature (phosphorylation of ATM targets). Radiosensitivity was not independently demonstrated for this variant to meet PS3_Moderate.	PMID:22213089 PMID:10873394
PS4	Not met	No case-control study meeting ATM VCEP PS4 criteria (p-value ≤0.05 AND odds ratio/relative risk ≥2 OR lower 95% CI ≥1.5) was identified for this variant. A Norwegian breast cancer screening study (PMID:11104561) included this variant in a mutation panel but detected no carriers among 483 patients.	PMID:11104561
PS5	N/A	Not included in ATM VCEP v1.5.0 criteria.
PM1	N/A	Marked Not Applicable by ATM VCEP v1.5.0.
PM2	Met	This variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0. The allele frequency of 0.0% is ≤0.001%, meeting the ATM VCEP PM2_Supporting threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	N/A	Skipped per adjudication instructions.
PM4	Not met	ATM VCEP PM4 is reserved for stop-loss variants. This variant is an in-frame deletion-insertion and does not create a stop-loss.
PM5	N/A	ATM VCEP PM5 applies to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with PVS1_VS(RNA). This variant is an in-frame deletion-insertion without PTC and without significant splicing impact (SpliceAI max delta = 0.12).	spliceai
PM6	N/A	Marked Not Applicable by ATM VCEP v1.5.0.
PP1	Not met	No segregation data available. ATM VCEP PP1 requires segregation analysis in AR condition (AT): ≥3 affected relatives for Strong, 2 for Moderate, 1 for Supporting. No published data on co-segregation of c.7875_7876delinsGC with disease in multiple affected relatives were identified.
PP2	N/A	Marked Not Applicable by ATM VCEP v1.5.0.
PP3	Not met	SpliceAI max delta score for this variant is 0.12, below the ATM VCEP PP3 threshold of ≥0.2 for splicing variants. REVEL score is not available as this is not a missense variant. Neither in-silico criterion threshold is met.	spliceai
PP4	N/A	Marked Not Applicable by ATM VCEP v1.5.0.
PP5	N/A	Not included in ATM VCEP v1.5.0 criteria.
BA1	Not met	Variant is absent from gnomAD v4.1. Grpmax filtering allele frequency is not >0.5%. Does not meet the ATM VCEP BA1 threshold.	gnomad_v4
BS1	Not met	Variant is absent from gnomAD v4.1. Grpmax filtering allele frequency is not >0.05%. Does not meet the ATM VCEP BS1 threshold.	gnomad_v4
BS2	N/A	Marked Not Applicable by ATM VCEP v1.5.0.
BS3	Not met	Functional evidence demonstrates loss of ATM function (absent kinase activity, absent protein), not rescue. ATM VCEP BS3 requires evidence that the variant rescues ATM-specific features and/or radiosensitivity. The available functional data show the opposite: abrogation of ATM kinase activity in homozygous state.	PMID:22213089 PMID:10873394
BS4	N/A	Marked Not Applicable by ATM VCEP v1.5.0.
BP1	N/A	Marked Not Applicable by ATM VCEP v1.5.0.
BP2	Not met	No co-occurrence data in trans with a known pathogenic variant was available for scoring under the ATM VCEP PM3/BP2 table. Without such observations, BP2 points cannot be assigned.
BP3	N/A	Marked Not Applicable by ATM VCEP v1.5.0.
BP4	Not met	SpliceAI max delta score is 0.12, which is above the ATM VCEP BP4 splicing threshold of ≤0.1. REVEL score is not available as this is not a missense variant. Neither in-silico benign criterion threshold is met.	spliceai
BP5	N/A	Marked Not Applicable by ATM VCEP v1.5.0.
BP6	N/A	Marked Not Applicable by ATM VCEP v1.5.0.
BP7	N/A	ATM VCEP BP7 is reserved for synonymous and deep intronic variants (further than +7 from donor or -21 from acceptor). This variant is an exonic in-frame deletion-insertion and does not qualify.

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