Variant classification summary

NM_000051.3:c.5544T>C

ATM · NP_000042.3:p.(Asp1848=) · NM_000051.3

GRCh37: chr11:108175449 T>C · GRCh38: chr11:108304722 T>C

Gene: ATM Transcript: NM_000051.3

Final call

VUS

PM2 supporting BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

ATM

Transcript

NM_000051.3

Protein

NP_000042.3:p.(Asp1848=)

gnomAD AF

6.1959327419109e-07 (v4.1)

ClinVar

Likely Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.3:c.5544T>C (NP_000042.3:p.(Asp1848=)) is a synonymous variant in ATM exon 36, assessed using the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) Expert Panel specifications for ATM v1.5.0.

2

The variant is absent or exceedingly rare in population databases: gnomAD v4.1 global allele frequency 6.20×10⁻⁷ (1/1,613,962 alleles, 0 homozygotes) and gnomAD v2.1 allele frequency 7.97×10⁻⁶ (2/251,006 alleles, 0 homozygotes), satisfying PM2_Supporting (≤0.001% cutoff).

3

SpliceAI predicts no significant splicing impact (max delta = 0.06), satisfying BP4_Supporting (SpliceAI ≤0.1 for no predicted splicing impact) under the CSPEC HBOP splicing rule.

4

BP7_Supporting is applied: the variant is a synonymous substitution located at c.5544, which lies 18 nucleotides from the donor splice site (beyond the +7 boundary) and 153 nucleotides from the acceptor splice site (beyond the -21 boundary), meeting the CSPEC definition for synonymous variants outside donor/acceptor site boundaries.

5

REVEL, BayesDel, and HCI Prior scores are not available for this synonymous variant, so the missense-specific in silico rules (PP3 missense, BP4 missense) are not applicable.

6

ClinVar classifies this variant as Likely Benign (VariationID 184944, reviewed by the ClinGen HBOP Expert Panel). The variant has been reported as Likely Benign by two clinical laboratories and Benign by one clinical laboratory.

7

No functional studies, case-control data, segregation data, or co-occurrence observations involving this specific variant were identified in the literature. Publications reviewed (PMID 34242744, 15604628, 17508274, 18163131, 20301317) did not contain variant-specific evidence for NM_000051.3:c.5544T>C.

8

Evidence summary: PM2_Supporting (1 pathogenic supporting) versus BP4_Supporting and BP7_Supporting (2 benign supporting). Under the CSPEC HBOP v1.5.0 combination rules, the presence of both pathogenic and benign supporting criteria triggers Rule 31, yielding a classification of Uncertain Significance — Conflicting Evidence.

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	N/A	Not applicable — the variant NM_000051.3:c.5544T>C is a synonymous substitution (NP_000042.3:p.(Asp1848=)) and does not fall into any null variant category (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion) required by the CSPEC HBOP ATM PVS1 decision tree.
PS1	Not met	CSPEC HBOP PS1 applies to missense variants or splice-altering variants with a known (likely) pathogenic comparator at the same nucleotide. This variant is synonymous and SpliceAI predicts no significant splice impact (max delta 0.06), so there is no applicable splicing comparator context. No known pathogenic variant at the same nucleotide with a similar predicted splicing defect has been identified.	spliceai
PS2	N/A	CSPEC HBOP v1.5.0 explicitly lists PS2 as Not Applicable for ATM variant interpretation.
PS3	Not assessed	No functional studies evaluating the impact of this specific synonymous variant on ATM protein function (phosphorylation of ATM-specific targets or radiosensitivity rescue) have been identified in the literature or functional databases.
PS4	Not assessed	No case-control studies evaluating this specific variant for enrichment in breast, ovarian, or pancreatic cancer cases versus controls have been identified. The CSPEC PS4 rule requires a case-control study with p≤0.05 and OR≥2 (or lower 95% CI ≥1.5).
PS5	N/A	CSPEC HBOP v1.5.0 does not define specifications for PS5 and PP5 is explicitly listed as Not Applicable. No CSPEC-recognized framework exists for applying PS5 to ATM variants.
PM1	N/A	CSPEC HBOP v1.5.0 explicitly lists PM1 as Not Applicable for ATM variant interpretation.
PM2	Met	The variant is exceedingly rare in population databases: gnomAD v4.1 overall allele frequency is 6.20×10⁻⁷ (1/1,613,962 alleles, 0 homozygotes), which is ≤0.001%, satisfying the CSPEC HBOP PM2_Supporting frequency threshold. In gnomAD v2.1, AF is 7.97×10⁻⁶ (2/251,006 alleles, 0 homozygotes).	gnomad_v2 gnomad_v4
PM5	N/A	CSPEC HBOP PM5 applies only to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047 or splice variants with NMD-prone PTC where PVS1_VS(RNA) is applied. This variant is synonymous and does not fall into either eligible category.
PM6	N/A	CSPEC HBOP v1.5.0 explicitly lists PM6 as Not Applicable for ATM variant interpretation.
PP1	Not assessed	No segregation data for this specific variant in families with ataxia-telangiectasia or cancer phenotypes has been identified. The CSPEC HBOP PP1 rules require documentation of AR-condition segregation in affected relatives.
PP2	N/A	CSPEC HBOP v1.5.0 explicitly lists PP2 as Not Applicable for ATM variant interpretation.
PP3	Not met	This variant is synonymous, so the missense REVEL rule (>0.7333) is not applicable. The CSPEC HBOP splicing rule requires SpliceAI ≥0.2 for predicted impact, but the variant has a maximum SpliceAI delta score of 0.06 (DS_AG=0.01, DS_AL=0.06, DS_DG=0.0, DS_DL=0.0), which does not meet the threshold for supporting pathogenicity via in silico splicing prediction.	spliceai
PP4	N/A	CSPEC HBOP v1.5.0 explicitly lists PP4 as Not Applicable for ATM variant interpretation.
PP5	N/A	CSPEC HBOP v1.5.0 explicitly lists PP5 as Not Applicable for ATM variant interpretation.
BA1	Not met	The CSPEC HBOP BA1 threshold requires Grpmax Filtering AF >0.5% in gnomAD v4. The variant's overall allele frequency in gnomAD v4.1 is 6.20×10⁻⁷ (0.000062%), and the highest subpopulation frequency (African/African American) is 1.33×10⁻⁵ (0.0013%). No population approaches the 0.5% BA1 cutoff.	gnomad_v4
BS1	Not met	The CSPEC HBOP BS1 threshold requires Grpmax Filtering AF >0.05% in gnomAD v4. The highest observed subpopulation frequency is 1.33×10⁻⁵ (0.0013%) in the African/African American population, well below 0.05%. The variant is too rare to satisfy BS1.	gnomad_v4
BS2	N/A	CSPEC HBOP v1.5.0 explicitly lists BS2 as Not Applicable for ATM variant interpretation.
BS3	Not assessed	No functional studies evaluating whether this synonymous variant rescues ATM-specific features (phosphorylation of ATM-specific targets) and/or radiosensitivity have been identified. The CSPEC BS3 rule requires experimental evidence demonstrating functional rescue.
BS4	N/A	CSPEC HBOP v1.5.0 explicitly lists BS4 as Not Applicable for ATM variant interpretation.
BP1	N/A	CSPEC HBOP v1.5.0 explicitly lists BP1 as Not Applicable for ATM variant interpretation.
BP2	Not assessed	No co-occurrence observations with known pathogenic ATM variants in unaffected (non-A-T) individuals are available to apply the CSPEC ATM PM3/BP2 point-based system for this specific variant.
BP3	N/A	CSPEC HBOP v1.5.0 explicitly lists BP3 as Not Applicable for ATM variant interpretation (in-frame deletions/insertions are not relevant to this synonymous substitution).
BP4	Met	SpliceAI predicts no significant splicing impact for this variant (maximum delta score = 0.06, which is ≤0.1), satisfying the CSPEC HBOP BP4_Supporting rule for no predicted splicing impact. REVEL is not applicable for this synonymous variant.	spliceai
BP5	N/A	CSPEC HBOP v1.5.0 explicitly lists BP5 as Not Applicable for ATM variant interpretation.
BP6	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely benign.	clinvar
BP7	Met	This is a synonymous variant (NP_000042.3:p.(Asp1848=)) located at c.5544 in exon 36 (c.5391–5562). The variant position is 18 nucleotides from the donor splice site (beyond the +7 boundary) and 153 nucleotides from the acceptor splice site (beyond the -21 boundary), satisfying the CSPEC HBOP BP7_Supporting definition for synonymous variants located outside donor/acceptor site boundaries. No RNA evidence for aberrant splicing exists to counter this assessment.	spliceai

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