ATMc.5544T>CUncertain significance

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Variant interpretation report

ATM c.5544T>C, p.(Asp1848=)

NM_000051.3:c.5544T>C NP_000042.3:p.(Asp1848=) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About ATM

No gene-level summary was recorded for this case.

Key facts

Evidence used: 3 supporting (benign) · 1 supporting (pathogenic)
Expert rules: ClinGen ATM VCEP v1.5.0
Other laboratories (ClinVar): 2 Likely benign · 1 Benign
Pipeline record: 31 May 2026

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): 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).
BP4 (supporting): 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.
BP6 (supporting): Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely benign.
BP7 (supporting): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is ClinGen ATM VCEP v1.5.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 3

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

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).

Benign criteria applied · 3

BP4Supporting

BP4 · supporting

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.

BP6Supporting

BP6 · supporting

Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely benign.

BP7Supporting

BP7 · supporting

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.

Recorded classification: Uncertain significance

Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

1 / 1,613,962 alleles

gnomAD v4.1: 1 / 1,613,962 alleles. Recorded AF 6.19593e-07. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.96794e-06; MAF= 0.00080%, 2/251006 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15233e-05; MAF= 0.00615%, 1/16254 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.060 maximum delta

Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

3 reported laboratory submissions

2 Likely benign · 1 Benign.

Applied · BP6 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen ATM VCEP v1.5.0, with the data and sources behind each one.

27 criteria with recorded statuses: 4 met · 4 not met · 5 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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).

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.

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.

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.

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.

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.

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.

Met · 4

PM2 SupportingThe 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). Details ▾Hide ▴

Evidence considered

gnomAD v4.1: AF=6.20×10⁻⁷ (1/1
613
962 alleles
0 hom)
gnomAD v2.1: AF=7.97×10⁻⁶ (2/251
006 alleles
Both datasets satisfy CSPEC PM2_Supporting threshold ≤0.001%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 SupportingSpliceAI 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.06 (≤0.1 threshold)
DS_AG=0.01
DS_AL=0.06
DS_DG=0.0
DS_DL=0.0
No splicing impact predicted

Sources

spliceai ↗

BP6 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely benign. Details ▾Hide ▴

Evidence considered

ClinVar expert panel classification

Sources

clinvar ↗

BP7 SupportingThis 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. Details ▾Hide ▴

Evidence considered

Synonymous variant NP_000042.3:p.(Asp1848=)
Exon 36: c.5391–5562
variant at c.5544
Distance to donor: 18 nt (>+7 boundary)
Distance to acceptor: 153 nt (>-21 boundary)
SpliceAI delta = 0.06 (no aberrant splicing predicted)

Sources

spliceai ↗

Not met · 4 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.06
no splicing impact predicted

Sources

spliceai ↗

PP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.06
does not meet CSPEC PP3 splicing threshold of ≥0.2
REVEL not applicable (synonymous variant)

Sources

spliceai ↗

BA1 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. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 global AF = 6.20×10⁻⁷ (0.000062%)
gnomAD v4.1 AFR max AF = 1.33×10⁻⁵ (0.0013%)
Both far below BA1 threshold of 0.5%

Sources

gnomad_v4 ↗

BS1 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. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AFR GF = 1.33×10⁻⁵ (0.0013%)
Below BS1 threshold of >0.05%

Sources

gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS3 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. Details ▾Hide ▴

Still missing

No functional assay data available for NM_000051.3:c.5544T>C

Sources

3424274415604628175082741816313120301317

PS4 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). Details ▾Hide ▴

Still missing

No case-control or large cohort studies for NM_000051.3:c.5544T>C

Sources

3424274415604628175082741816313120301317

PP1 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. Details ▾Hide ▴

Still missing

No segregation/family data available for NM_000051.3:c.5544T>C

Sources

3424274415604628175082741816313120301317

BS3 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. Details ▾Hide ▴

Still missing

No functional rescue assays available for NM_000051.3:c.5544T>C

Sources

3424274415604628175082741816313120301317

BP2 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. Details ▾Hide ▴

Still missing

No co-occurrence data in unaffected individuals available

Sources

3424274415604628175082741816313120301317

Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/ANot 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. Details ▾Hide ▴