Variant classification summary

NM_000051.4:c.7974T>C

ATM · NP_000042.3:p.(Asn2658=) · NM_000051.4

GRCh37: chr11:108204659 T>C · GRCh38: chr11:108333932 T>C

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Asn2658=)

gnomAD AF

3.10205641523879e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.7974T>C is a synonymous variant p.(Asn2658=) in ATM exon 54, located well outside the canonical splice consensus regions.

2

SpliceAI predicts no splice impact (max delta score = 0.00).

3

This variant is present in gnomAD v4.1 at very low frequency (total AF = 0.00031%, 5/1,611,834 alleles, 0 homozygotes), highest in East Asian population (sub-population AF = 0.011%).

4

ClinVar reports this variant as Likely benign (4 clinical laboratories) and Benign (1 laboratory); review status: criteria provided, single submitter (ClinVar Variation ID: 414583).

5

The ClinGen HBOP VCEP supplementary table (PMID:40580951, Table S1) classifies this variant as Likely benign with an eDA score of 3.10e-06.

6

BP7_Supporting is met: synonymous variant outside donor +7 and acceptor -21 splice regions with no predicted splice impact (SpliceAI = 0.0).

7

BP4_Supporting is met: no predicted impact via splicing (SpliceAI max delta = 0.0 ≤ 0.1). Note partial overlap with BP7.

8

PM2_Supporting is met: gnomAD v4.1 total allele frequency (0.00031%) is ≤ 0.001% VCEP threshold. Per VCEP guidance, PM2 is not considered conflicting evidence for variants that otherwise are likely benign/benign.

9

No pathogenic criteria beyond PM2_Supporting are met. Multiple benign supporting criteria (BP7, BP4) are met with no conflicting pathogenic evidence per VCEP PM2 guidance.

10

The ClinGen HBOP Expert Panel classification from the VCEP supplementary table is Likely benign, which is concordant with the evidence-based assessment.

Final determination: Rule19 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 Benign.

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	Not a null variant. NM_000051.4:c.7974T>C is a synonymous substitution p.(Asn2658=); PVS1 is restricted to nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon deletion variants per VCEP ATM PVS1 decision tree.	vcep_atm_pvs1_1_5
PS1	N/A	Synonymous variant p.(Asn2658=) does not alter the amino acid. PS1 requires the same amino acid change as a known pathogenic missense variant. Splice defect has been ruled out (SpliceAI max delta = 0.0).	vcep_atm_ps1_1_5 spliceai
PS2	N/A	VCEP ATM v1.5: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed.'	cspec
PS3	Not assessed	No well-established in vitro or in vivo functional studies identified for this variant. The VCEP ATM kinase activity and radiosensitivity assay reference tables do not list c.7974T>C. No variant-specific functional data found in literature.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not assessed	No case-control studies demonstrating statistically significant enrichment of this variant in affected individuals versus controls are available. Literature review identified only general guidelines and review papers, none reporting variant-specific case-control data.
PS5	N/A	PS5 is not a standard ACMG/AMP criterion. The standard criteria set includes PVS1, PS1-PS4, PM1-PM6, PP1-PP5. There is no PS5 criterion in the ACMG/AMP 2015 framework (PMID:25741868).	PMID:25741868
PM1	N/A	VCEP ATM v1.5: 'Do not use: Benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time.'	cspec
PM2	Met	This variant is present at very low frequency in gnomAD v4.1 (total AF = 0.00031%, 5/1,611,834 alleles, 0 homozygotes), meeting the VCEP PM2_Supporting threshold of ≤0.001%. Observed predominantly in the East Asian population (sub-population AF = 0.011%). Per VCEP guidance, PM2 is not considered conflicting evidence for variants that otherwise are likely benign/benign.	gnomad_v4 cspec
PM5	N/A	VCEP ATM v1.5 PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with NMD-prone PTCs upstream of p.Arg3047. c.7974T>C is a synonymous variant with no PTC.	cspec pm5_candidates
PM6	N/A	VCEP ATM v1.5: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.'	cspec
PP1	Not assessed	No co-segregation data available for this variant. The VCEP restricts PP1 for ATM to AR condition only (segregation in A-T families). No A-T family segregation data identified.
PP2	N/A	VCEP ATM v1.5: 'Do not use: ATM does not have a defined low rate of missense benign variation.' Additionally, this is a synonymous variant, not missense.	cspec
PP3	Not met	SpliceAI predicts no splice impact (max delta = 0.0), failing the VCEP PP3 threshold of SpliceAI ≥0.2 for silent variants. REVEL score is unavailable for synonymous variants. No multiple lines of computational evidence support a deleterious effect.	spliceai
PP4	N/A	VCEP ATM v1.5: 'Autosomal Dominant: do not use as breast cancer is a disease with multiple genetic etiology. Autosomal Recessive: do not use as a separate line of evidence. Such evidence is built into the Ataxia Telangiectasia PM3\|BP2 table.'	cspec
PP5	Not met	The ClinGen HBOP VCEP supplementary table (PMID:40580951) classifies this variant as Likely benign. ClinVar lists this variant as Likely benign (4 clinical laboratories) and Benign (1 laboratory). No reputable source has reported this variant as pathogenic. PP5 requires a pathogenic assertion from a reputable source.	clinvar vcep_suppl_tables1_pmid_40580951
BA1	Not met	gnomAD v4.1 grpmax filtering AF = 0.00435%, which does not exceed the VCEP BA1 threshold of >0.5%.	gnomad_v4 cspec
BS1	Not met	gnomAD v4.1 grpmax filtering AF = 0.00435%, which does not exceed the VCEP BS1 threshold of >0.05%.	gnomad_v4 cspec
BS2	N/A	VCEP ATM v1.5: 'Do not use: ATM has incomplete penetrance.'	cspec
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating normal protein function or splicing for this variant. The VCEP ATM kinase activity and radiosensitivity reference tables (clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx) do not include c.7974T>C.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	VCEP ATM v1.5: lack of co-segregation analysis not applicable. AD condition: co-segregation in low-penetrance genes can lead to false positives. AR condition: informative instances too rare.	cspec
BP1	N/A	VCEP ATM v1.5: 'Do not use: Missense pathogenic variants are known for ATM.'	cspec
BP2	Not assessed	No evidence of this variant observed in trans with a pathogenic ATM variant in unaffected individuals (≥18 years, no A-T). No homozygous unaffected individuals identified. The VCEP BP2 point-based system requires specific proband-level data not available in the evidence sources provided.	cspec vcep_atm_pm3_bp2_1_5
BP4	Met	SpliceAI predicts no splice impact (max delta = 0.0), meeting the VCEP BP4 threshold of SpliceAI ≤0.1 for splicing prediction. Multiple lines of computational evidence (SpliceAI) suggest no impact on splicing. REVEL not available for synonymous variants. Note: BP4 and BP7 both draw from the same underlying observation of absent splice impact; applied together they may overlap.	spliceai cspec
BP5	N/A	VCEP ATM v1.5: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype. ATM has low penetrance and will naturally occur with other pathogenic variants more frequently.'	cspec
BP6	N/A	VCEP ATM v1.5: 'Not Applicable for this VCEP' — 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BP7	Met	NM_000051.4:c.7974T>C is a synonymous variant p.(Asn2658=) located in exon 54 (c.7939-c.8077). The variant is 35 nucleotides downstream of the acceptor site and 103 nucleotides upstream of the donor site, placing it well outside the VCEP-defined splice consensus regions (+7 donor, -21 acceptor). SpliceAI predicts no splice impact (max delta = 0.0). VCEP BP7 criteria for synonymous variants are met.	spliceai cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.