Variant classification summary

NM_000051.4:c.5600A>G

ATM · NP_000042.3:p.(Gln1867Arg) · NM_000051.4

GRCh37: chr11:108175505 A>G · GRCh38: chr11:108304778 A>G

Gene: ATM Transcript: NM_000051.4

Final call

PS3 supporting PM2 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Gln1867Arg)

gnomAD AF

1.8588005531790446e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.5600A>G (p.Gln1867Arg) is a missense variant in exon 37 of ATM. It has been reported in ClinVar as a variant of uncertain significance (ClinVar ID 453589, 4 clinical laboratories).

2

This variant is present in gnomAD v4.1 at an extremely low allele frequency (AF = 1.86e-6, 3/1,613,944 alleles, 0 homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada, meeting the ATM VCEP PM2_Supporting threshold (≤0.001%).

3

The ATM VCEP supplementary functional data (Suppl_TableS1, PMID 40580951) classifies this variant as 'Non-functional' (combined score -2.05, Medium-high confidence), meeting PS3_Supporting per the VCEP framework for variants that fail to rescue ATM-specific functional features.

4

Multiple computational predictors suggest a benign effect: REVEL score 0.088 (meeting BP4_Supporting threshold ≤0.249), BayesDel -0.34033, AlphaMissense 0.0758. SpliceAI predicts no splicing impact (max delta 0.10, meeting BP4 splicing threshold ≤0.1).

5

No case-control studies, co-segregation data, or confirmed de novo observations have been identified for this variant. A ClinVar submission noting observation in trans with a pathogenic ATM variant in an A-T patient was not accompanied by peer-reviewed publication, precluding application of PM3.

6

The variant has not been reported in COSMIC and is not located in a statistically significant cancer hotspot residue.

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	PVS1 is applicable only to null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, exon deletions). NM_000051.4:c.5600A>G is a missense variant (p.Gln1867Arg) and does not meet the VCEP ATM PVS1 decision tree entry criteria. SpliceAI max delta score is 0.10, confirming no cryptic splice-altering effect.	spliceai vcep_atm_pvs1_1_5
PS1	Not met	PS1 requires the same amino acid change (p.Gln1867Arg) to be produced by a different nucleotide change already classified as pathogenic or likely pathogenic. Review of ClinVar and VCEP supplementary tables identified no alternative nucleotide variant encoding p.Q1867R with a P/LP classification. Adjacent missense changes at codon 1867 (p.Q1867K, p.Q1867E, p.Q1867P, p.Q1867L, p.Q1867H) are not the same amino acid change.	vcep_suppl_tables1_pmid_40580951 clinvar
PS2	N/A	The ATM VCEP v1.5.0 does not use PS2 for autosomal dominant or autosomal recessive disease; informative de novo occurrences have not been observed for ATM and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Met	The ATM VCEP supplementary functional data (Suppl_TableS1, PMID 40580951) classifies NM_000051.4:c.5600A>G (p.Q1867R) as 'Non-functional' with Medium-high confidence based on a combined function score of -2.05 integrating multiple functional predictors. This meets the VCEP PS3_Supporting threshold for a variant that fails to rescue an ATM-specific functional feature. No direct experimental rescue assay data (kinase activity or radiosensitivity) from the VCEP-approved functional studies (Mitui 2009, Barone 2009, Scott 2002) was identified for this exact variant.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not met	The ATM VCEP requires case-control studies demonstrating a statistically significant enrichment (p ≤ 0.05 AND OR ≥ 2 or lower 95% CI ≥ 1.5). No case-control study or proband-counting analysis for NM_000051.4:c.5600A>G has been identified in the literature or ClinVar submissions. The variant has been reported in ClinVar as Uncertain significance and is extremely rare in gnomAD, but population frequency data alone cannot substitute for a formal case-control comparison.	clinvar gnomad_v4
PS5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; this criterion is not applicable for this VCEP.	cspec
PM1	N/A	The ATM VCEP does not use PM1; benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined for ATM at this time.	cspec
PM2	Met	NM_000051.4:c.5600A>G is present at an extremely low frequency in gnomAD v4.1 (AF = 1.8588e-06, 0.000186%, 3/1,613,944 alleles, 0 homozygotes). This is below the VCEP PM2_Supporting threshold of ≤0.001% (≤1e-5). The variant is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v4 gnomad_v2
PM5	N/A	The ATM VCEP restricts PM5 to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, and splice variants with PTC upstream of p.Arg3047 where PVS1(RNA) is applied. Missense changes are explicitly excluded: 'Do not use for missense changes.' NM_000051.4:c.5600A>G is a missense variant (p.Gln1867Arg).	cspec pm5_candidates
PM6	N/A	The ATM VCEP v1.5.0 does not use PM6 for autosomal dominant or autosomal recessive disease; informative de novo occurrences have not been observed for ATM and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not met	The ATM VCEP applies PP1 only for autosomal recessive conditions (Ataxia-Telangiectasia) and requires segregation of both variants in affected relatives. No published segregation data or family studies involving NM_000051.4:c.5600A>G have been identified in the literature or ClinVar submissions.	clinvar
PP2	N/A	The ATM VCEP does not use PP2; ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Not met	The ATM VCEP PP3 threshold for missense variants is REVEL > 0.7333. The REVEL score for NM_000051.4:c.5600A>G (p.Q1867R) is 0.088, well below this threshold. The SpliceAI max delta score is 0.10, below the VCEP splicing threshold of ≥0.2. Multiple computational predictors (BayesDel -0.34033, AlphaMissense 0.0758) are consistent with a benign or non-damaging prediction.	revel bayesdel spliceai
PP4	N/A	The ATM VCEP does not use PP4. For autosomal dominant disease: breast cancer has multiple genetic etiologies and no features distinguish hereditary from sporadic cases. For autosomal recessive: such evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; this criterion is not applicable for this VCEP.	cspec
BA1	Not met	The ATM VCEP BA1 threshold requires a Grpmax Filtering AF > 0.5% in the gnomAD v4 dataset. NM_000051.4:c.5600A>G has an overall allele frequency of 0.000186% (1.8588e-06) in gnomAD v4.1, far below the BA1 stand-alone benign threshold. The grpmax filtering allele frequency is not available (null), but the total AF is orders of magnitude below the BA1 cutoff.	gnomad_v4
BS1	Not met	The ATM VCEP BS1 threshold requires a Grpmax Filtering AF > 0.05% in gnomAD v4. The overall allele frequency is 0.000186%, and the grpmax filtering AF is unavailable (null). The total frequency is far below the BS1 threshold.	gnomad_v4
BS2	N/A	The ATM VCEP does not use BS2 because ATM has incomplete penetrance.	cspec
BS3	Not met	The ATM VCEP BS3 requires a well-established functional assay demonstrating no damaging effect (variant rescues ATM function). The Suppl_TableS1 (PMID 40580951) classifies NM_000051.4:c.5600A>G as 'Non-functional' with Medium-high confidence, indicating the variant fails to rescue function — the opposite of what BS3 requires. Additionally, multiple in silico predictors (REVEL 0.088, BayesDel -0.34033, AlphaMissense 0.0758) suggest a benign/non-damaging effect, but in silico predictions alone do not meet the VCEP BS3 threshold for well-established functional evidence.	vcep_suppl_tables1_pmid_40580951 revel bayesdel
BS4	N/A	The ATM VCEP does not use BS4. For AD: co-segregation analysis in low-penetrance genes can lead to false positives. For AR: informative instances of lack of co-segregation in A-T families are too rare to be considered.	cspec
BP1	N/A	The ATM VCEP does not use BP1; missense pathogenic variants are known for ATM.	cspec
BP2	Not met	The ATM VCEP BP2 requires observation of the variant in cis with a pathogenic/likely pathogenic variant in an unaffected individual aged ≥18 years with no evidence of A-T, scored via the PM3/BP2 points table. No such phasing data or unaffected individual observations have been identified for NM_000051.4:c.5600A>G. A ClinVar submission noting co-occurrence in trans with a pathogenic variant in an A-T patient is the opposite configuration (supports PM3, not BP2).	clinvar vcep_atm_pm3_bp2_1_5
BP4	Met	The ATM VCEP BP4 threshold for missense variants is REVEL ≤ 0.249. NM_000051.4:c.5600A>G (p.Q1867R) has a REVEL score of 0.088, meeting the BP4_Supporting threshold. Additionally, the SpliceAI max delta score is 0.10, which is ≤0.1, meeting the VCEP BP4 splicing threshold (no predicted splicing impact). BayesDel score of -0.34033 also supports a benign computational prediction.	revel bayesdel spliceai
BP5	N/A	The ATM VCEP does not use BP5; cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance with higher tolerance in the general population.	cspec
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; this criterion is not applicable for this VCEP.	cspec
BP7	N/A	The ATM VCEP restricts BP7 to synonymous and deep intronic variants (further than +7 at donor and -21 at acceptor sites). NM_000051.4:c.5600A>G is a missense variant (p.Gln1867Arg) located in exon 37 and does not qualify for BP7.	cspec spliceai

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