Variant classification summary

NM_000051.4:c.4850T>C

ATM · NP_000042.3:p.(Leu1617Pro) · NM_000051.4

GRCh37: chr11:108165727 T>C · GRCh38: chr11:108295000 T>C

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PS3 supporting PM2 supporting PP3 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Leu1617Pro)

gnomAD AF

6.195717767707671e-07 (v4.1)

ClinVar

Uncertain Significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: Direct prime-editing data classify c.4850T>C as non-functional with high confidence.

2

PM2 supporting: The highest observed gnomAD subpopulation allele frequency is below the ATM VCEP threshold of 0.001%.

3

PP3 supporting: REVEL is 0.901, exceeding the ATM VCEP missense threshold of 0.7333.

4

BP4 supporting: SpliceAI maximum delta is 0.023, below the ATM VCEP no-impact threshold of 0.1.

Final determination: Under the ATM VCEP Version 1.6 Rule19, Likely Pathogenic requires one Very Strong criterion from the specified set plus exactly one listed Supporting criterion; neither that rule nor any benign rule is satisfied here.

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 applicable: c.4850T>C is a missense variant, whereas the ATM PVS1 guide limits this criterion to null variant classes such as nonsense, frameshift, splice-site, initiation-codon, or exon-deletion variants.	cspec vcep_atm_pvs1_1_6 PMID:22649200
PS1	Not assessed	Not assessed: no previously established pathogenic variant with the same amino-acid change was identified for comparison under the ATM PS1 rule.	vcep_atm_ps1_1_6 PMID:22649200
PS2	N/A	Not applicable: the ATM VCEP excludes PS2 for autosomal dominant and autosomal recessive disease because informative de novo occurrences have not been observed.	cspec
PS3	Met	Met at Supporting: Table S1 directly measures c.4850T>C as Non-functional with High confidence and DeepATM_predicted=No.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 PMID:22649200
PS4	Not assessed	Not assessed: one affected patient is reported, but no control comparison, p-value, odds ratio, or 95% confidence interval is available for the VCEP PS4 rule.	cspec PMID:22649200
PM1	N/A	Not applicable: the ATM VCEP marks PM1 Not Applicable, so residue 1617 is not evaluated through a PM1 domain or hotspot route.	cspec
PM2	Met	Met at Supporting: highest gnomAD subpopulation AF is 8.475107760995181e-07 (0.0000847511%), below the VCEP threshold of 0.001%.	cspec gnomad_v4
PM3	Not assessed	Not assessed: one confident A-T proband contributes 2.0 phase-unknown points, but the reported second variant's VCEP classification and phase are unconfirmed.	vcep_atm_pm3_bp2_1_6 PMID:22649200
PM4	N/A	Not applicable: p.(Leu1617Pro) is a missense change, and the ATM VCEP PM4 rule applies only to stop-loss variants.	cspec
PM5	N/A	Not applicable: PM5 is limited to NMD-prone truncating or qualifying observed splice variants upstream of p.Leu3048, whereas this variant is missense.	cspec
PM6	N/A	Not applicable: the ATM VCEP excludes assumed de novo evidence for autosomal dominant and autosomal recessive disease in this framework.	cspec
PP1	Not assessed	Not assessed: one affected patient carried the variant and c.6916delAG, but no affected-relative segregation or parental-phase data were reported.	cspec PMID:22649200
PP2	N/A	Not applicable: the ATM VCEP marks PP2 Not Applicable, so no gene-level missense-enrichment evidence is assigned.	cspec
PP3	Met	Met: REVEL 0.901 exceeds the ATM VCEP PP3 missense threshold of >0.7333.	cspec revel vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4	N/A	Not applicable: the ATM VCEP excludes PP4 for breast cancer and incorporates autosomal-recessive phenotype evidence into PM3/BP2 instead.	cspec
PP5	N/A	Not applicable: the ATM VCEP explicitly prohibits PP5, regardless of pathogenic reports from reputable sources.	cspec
BA1	Not assessed	Not assessed: the required gnomAD Grpmax Filtering AF is unavailable, although the highest observed subpopulation AF is 8.475107760995181e-07.	cspec gnomad_v4
BS1	Not assessed	Not assessed: the required gnomAD Grpmax Filtering AF is unavailable, although the highest observed subpopulation AF is 8.475107760995181e-07.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP explicitly marks BS2 as not applicable.	cspec
BS3	Not met	Not met: Table S1 directly classifies c.4850T>C as Non-functional, not Functional, so the VCEP rescue requirement for BS3 is not satisfied.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 PMID:22649200
BS4	N/A	Not applicable: the ATM VCEP states that informative lack-of-co-segregation instances in ataxia-telangiectasia families are too rare to receive weight.	cspec
BP1	N/A	Not applicable: the ATM VCEP marks BP1 Not Applicable, so no benign missense-gene or domain evidence is assigned.	cspec
BP2	Not assessed	Not assessed: the available affected-patient report does not establish cis phase or an unaffected adult observation required for the BP2 points table.	vcep_atm_pm3_bp2_1_6
BP3	N/A	Not applicable: the ATM VCEP explicitly marks BP3 as Not Applicable, regardless of this missense variant's repeat-region context.	cspec
BP4	Met	Met: SpliceAI max delta 0.023 is below the ATM VCEP BP4 no-impact threshold of <=0.1.	cspec spliceai revel vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5	N/A	Not applicable: the ATM VCEP prohibits BP5 because multiple pathogenic variants may coexist without a noticeable phenotype difference in this low-penetrance gene.	cspec
BP6	N/A	Not applicable: the ATM VCEP explicitly prohibits BP6, regardless of benign reports from reputable sources.	cspec
BP7	N/A	Not applicable: BP7 is restricted by the ATM VCEP to synonymous and deep intronic variants, not missense substitutions.	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.