Variant classification summary

NM_000051.4:c.6801C>T

ATM · NP_000042.3:p.(Asn2267=) · NM_000051.4

GRCh37: chr11:108196265 C>T · GRCh38: chr11:108325538 C>T

Gene: ATM Transcript: NM_000051.4

Final call

PM2 supporting BP7 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Asn2267=)

gnomAD AF

2.5026340223084796e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The ATM c.6801C>T (p.Asn2267=; p.N2267=) variant has been reported in ClinVar as likely benign or benign by three clinical laboratory submissions.

2

This variant is absent from gnomAD v2.1 and gnomAD-Canada and is present at very low frequency in gnomAD v4.1 (4/1,598,316 alleles; AF 0.00025%), which meets the ATM VCEP PM2_Supporting rarity threshold.

3

SpliceAI predicts no significant splice impact for this synonymous variant (max delta score 0.00), supporting BP7 and not supporting PP3.

Final determination: Rule31 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 Uncertain Significance - Conflicting Evidence.

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 variant is a synonymous substitution, p.(Asn2267=) / p.(N2267=), and does not fall into the ATM PVS1 null-variant categories or the generic canonical ±1,2 splice consensus categories, so PVS1 is not applicable.	cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No evidence was identified that this variant produces the same predicted or observed splice defect as a known pathogenic or likely pathogenic ATM variant, so PS1 is not met.	cspec vcep_atm_ps1_1_5 spliceai
PS2	N/A	The ATM VCEP marks PS2 as not applicable for this framework.	cspec
PS3	Not assessed	No published functional study was identified showing that this variant fails ATM-specific rescue assays, so PS3 was not assessed.	cspec
PS4	Not assessed	No case-control data were identified showing enrichment of this variant in affected individuals, so PS4 was not assessed.	cspec
PM1	N/A	The ATM VCEP marks PM1 as not applicable for this framework.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (4/1,598,316 alleles; AF 0.00025%), which is below the ATM VCEP PM2 threshold of 0.001%. The highest observed subpopulation count is a single allele in the Remaining individuals population (1/62,100; AF 0.00161%), and the ATM VCEP notes that n=1 in a single subpopulation is sufficiently rare for PM2_Supporting.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant has been observed in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia, so PM3 was not assessed.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	This variant is not a stop-loss variant, so PM4 is not applicable.	cspec
PM5	N/A	Under the ATM VCEP, PM5 is used for truncating or qualifying splice variants upstream of p.Arg3047 rather than classic same-residue missense logic, and this synonymous variant does not meet that rule.	cspec pm5_candidates
PM6	N/A	The ATM VCEP marks PM6 as not applicable for 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 VCEP marks PP2 as not applicable for this framework.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which is below the ATM VCEP PP3 splicing threshold of 0.2. No additional calibrated predictor score supporting pathogenicity was available for this synonymous change.	cspec spliceai
PP4	N/A	The ATM VCEP marks PP4 as not applicable for this framework.	cspec
PP5	N/A	The ATM VCEP marks PP5 as not applicable for this framework.	cspec
BA1	Not met	The highest observed filtering allele frequency in gnomAD v4.1 is 6.8e-07 (0.000068%), which is far below the ATM VCEP BA1 threshold of greater than 0.5%, so BA1 is not met.	cspec gnomad_v4
BS1	Not met	The highest observed filtering allele frequency in gnomAD v4.1 is 6.8e-07 (0.000068%), which is below the ATM VCEP BS1 threshold of greater than 0.05%, so BS1 is not met.	cspec gnomad_v4
BS2	N/A	The ATM VCEP marks BS2 as not applicable for this framework.	cspec
BS3	Not assessed	No published functional study was identified showing rescue of ATM-specific function or radiosensitivity for this variant, so BS3 was not assessed.	cspec
BS4	N/A	The ATM VCEP marks BS4 as not applicable for this framework.	cspec
BP1	N/A	The ATM VCEP marks BP1 as not applicable for this framework.	cspec
BP2	Not assessed	No evidence was identified that this variant co-occurs in trans with a pathogenic ATM variant in an unaffected individual, so BP2 was not assessed.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	The ATM VCEP marks BP3 as not applicable for this framework.	cspec
BP4	Not assessed	SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which is below the ATM VCEP BP4 threshold of 0.1, but this silent variant is more specifically addressed by BP7 and BP4 was not counted separately to avoid double counting the same computational evidence.	cspec spliceai
BP5	N/A	The ATM VCEP marks BP5 as not applicable for this framework.	cspec
BP6	N/A	The ATM VCEP marks BP6 as not applicable for this framework.	cspec
BP7	Met	This variant is a synonymous substitution, p.(Asn2267=) / p.(N2267=), and SpliceAI predicts no significant splice impact (max delta score 0.00), supporting BP7 for a silent ATM variant.	cspec spliceai

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