ATMc.6200C>ALikely pathogenic

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Variant interpretation report

ATM c.6200C>A, p.(Ala2067Asp)

NM_000051.4:c.6200C>A NP_000042.3:p.(Ala2067Asp) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely pathogenic classification under the recorded framework.

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: 1 strong (pathogenic) · 2 supporting (pathogenic)
Expert rules: ClinGen ATM VCEP v1.5.0
Other laboratories (ClinVar): 11 Pathogenic · 5 Likely pathogenic · 1 pathogenic
Pipeline record: 24 May 2026

Evidence considered

View criteria

Applied evidence criteria

PS3 (supporting): In a published functional study, lymphoblastoid cells from affected individuals expressed only small amounts of ATM protein, showed no ATM Ser1981 autophosphorylation, and had trace-to-absent phosphorylation of downstream ATM targets; engineered cells expressing the variant also showed trace-to-absent downstream signaling. This demonstrates failure of an ATM-specific functional feature and supports PS3 at supporting strength.
PM2 (supporting): This variant is very rare in gnomAD v4.1, with a total allele frequency of 3.10452e-06 (0.00031%), 5 of 1610556 alleles observed, no homozygotes, and grpmax filtering allele frequency 8e-07. This is below the ATM PM2 threshold of 0.001%, supporting PM2 at supporting strength.
PM3 (strong): This variant has been reported in multiple affected individuals with variant ataxia-telangiectasia, including homozygous affected members in Canadian Mennonite families. Under the ATM PM3 framework, homozygous affected individuals can contribute points up to the cap of two individuals; this supports PM3 at strong strength.

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: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PS3Supporting

PS3 · supporting

In a published functional study, lymphoblastoid cells from affected individuals expressed only small amounts of ATM protein, showed no ATM Ser1981 autophosphorylation, and had trace-to-absent phosphorylation of downstream ATM targets; engineered cells expressing the variant also showed trace-to-absent downstream signaling. This demonstrates failure of an ATM-specific functional feature and supports PS3 at supporting strength.

PM2Supporting

PM2 · supporting

This variant is very rare in gnomAD v4.1, with a total allele frequency of 3.10452e-06 (0.00031%), 5 of 1610556 alleles observed, no homozygotes, and grpmax filtering allele frequency 8e-07. This is below the ATM PM2 threshold of 0.001%, supporting PM2 at supporting strength.

PM3Strong

PM3 · strong

This variant has been reported in multiple affected individuals with variant ataxia-telangiectasia, including homozygous affected members in Canadian Mennonite families. Under the ATM PM3 framework, homozygous affected individuals can contribute points up to the cap of two individuals; this supports PM3 at strong strength.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule12 (1 Pathogenic.Strong + Pathogenic.Supporting >=2) with applied criteria: PM3 strong, PM2 supporting, PS3 supporting; maps to Likely Pathogenic.

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

5 / 1,610,556 alleles

gnomAD v4.1: 5 / 1,610,556 alleles. Recorded AF 3.10452e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97905e-06; MAF= 0.00040%, 1/251316 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79647e-06; MAF= 0.00088%, 1/113682 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

17 reported laboratory submissions

11 Pathogenic · 5 Likely pathogenic · 1 pathogenic.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV53741904, n = 2 times).

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.

28 criteria with recorded statuses: 3 met · 6 not met · 3 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

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

Met Not met Not assessed Not applicable

The ATM c.6200C>A (p.Ala2067Asp; p.A2067D) variant has been reported in ClinVar with multiple pathogenic and likely pathogenic germline submissions, and variant-specific cancer curation has linked it to literature consistent with loss of ATM function.

This variant is very rare in population databases, with gnomAD v4.1 showing an allele frequency of 3.10452e-06 (5/1610556 alleles), no homozygotes, and grpmax filtering allele frequency 8e-07, which supports rarity for ATM.

In a published functional study, patient-derived and engineered cells showed markedly reduced ATM protein, absent ATM Ser1981 autophosphorylation, and trace-to-absent phosphorylation of downstream ATM targets, supporting a damaging effect on ATM function.

Computational evidence does not meet the ATM PP3 or BP4 missense thresholds: REVEL is 0.435, BayesDel is 0.0616905, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01.

Met · 3

PS3 SupportingIn a published functional study, lymphoblastoid cells from affected individuals expressed only small amounts of ATM protein, showed no ATM Ser1981 autophosphorylation, and had trace-to-absent phosphorylation of downstream ATM targets; engineered cells expressing the variant also showed trace-to-absent downstream signaling. This demonstrates failure of an ATM-specific functional feature and supports PS3 at supporting strength. Details ▾Hide ▴

Rule

ATM PS3_Supporting when a variant fails to rescue an ATM-specific feature; moderate requires failure to rescue both ATM-specific feature and radiosensitivity.

Evidence considered

PMID:25077176 functional assays showed markedly impaired ATM protein expression and ATM-specific signaling.

Still missing

A qualifying assay demonstrating failure to rescue both ATM-specific signaling and radiosensitivity was not confirmed from the available evidence for moderate strength.

Sources

cspec ↗PMID:25077176 ↗

PM2 SupportingThis variant is very rare in gnomAD v4.1, with a total allele frequency of 3.10452e-06 (0.00031%), 5 of 1610556 alleles observed, no homozygotes, and grpmax filtering allele frequency 8e-07. This is below the ATM PM2 threshold of 0.001%, supporting PM2 at supporting strength. Details ▾Hide ▴

Rule

ATM PM2_Supporting for frequency ≤0.001% in gnomAD v4.

Evidence considered

gnomAD v4.1 total AF 3.10452e-06
5/1610556 alleles
0 homozygotes.
gnomAD v4.1 grpmax FAF 8e-07.

Sources

gnomad_v4 ↗cspec ↗

PM3 StrongThis variant has been reported in multiple affected individuals with variant ataxia-telangiectasia, including homozygous affected members in Canadian Mennonite families. Under the ATM PM3 framework, homozygous affected individuals can contribute points up to the cap of two individuals; this supports PM3 at strong strength. Details ▾Hide ▴

Rule

ATM PM3 point system; homozygous affected individuals may contribute up to the two-individual cap.

Evidence considered

PM3 table allows homozygous affected individuals
maximum two individuals.
PMID:22345219 reported 13 members from 3 families with the homozygous ATM founder mutation and variant A-T.
PMID:25077176 described 10 Mennonite patients carrying the variant with variant A-T.

Sources

cspec ↗vcep_atm_pm3_bp2_1_5PMID:25077176 ↗PMID:22345219 ↗

Not met · 6 · evaluated, threshold not reached

PS1 No previously established pathogenic ATM variant producing the same amino acid substitution was identified from the available evidence, so PS1 is not met. Details ▾Hide ▴

Rule

Same amino acid change as a previously established pathogenic variant, with splicing ruled out.

Evidence considered

No qualifying same-amino-acid comparator was identified in the reviewed materials.

Sources

cspec ↗vcep_atm_ps1_1_5clinvar ↗

PP3 For this missense variant, the REVEL score is 0.435, which is below the ATM PP3 threshold of greater than 0.7333. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, which is below the splice-impact threshold of 0.2. These results do not support PP3. Details ▾Hide ▴

Rule

Missense REVEL >0.7333 or splice-impact prediction SpliceAI ≥0.2.

Evidence considered

REVEL 0.435.
SpliceAI max delta 0.01.

Sources

cspec ↗revelspliceai ↗

BA1 The gnomAD v4.1 grpmax filtering allele frequency is 8e-07, which is far below the ATM BA1 threshold of greater than 0.5%. Details ▾Hide ▴

Rule

Grpmax filtering AF >0.5% in gnomAD v4.

Evidence considered

gnomAD v4.1 grpmax FAF 8e-07.
ATM BA1 threshold: >0.5%.

Sources

gnomad_v4 ↗cspec ↗

BS1 The gnomAD v4.1 grpmax filtering allele frequency is 8e-07, which is well below the ATM BS1 threshold of greater than 0.05%. Details ▾Hide ▴

Rule

Grpmax filtering AF >0.05% in gnomAD v4.

Evidence considered

gnomAD v4.1 grpmax FAF 8e-07.
ATM BS1 threshold: >0.05%.

Sources

gnomad_v4 ↗cspec ↗

BS3 Available functional evidence does not show rescue of ATM function. In a published functional study, patient-derived and engineered cells showed markedly reduced ATM protein with absent ATM autophosphorylation and trace-to-absent phosphorylation of downstream ATM targets, which argues against BS3. Details ▾Hide ▴

Rule

BS3 requires rescue of ATM-specific feature(s) and/or radiosensitivity, depending on strength.

Evidence considered

PMID:25077176 reported no ATM Ser1981 autophosphorylation and trace-to-absent transphosphorylation of downstream ATM targets.

Sources

cspec ↗PMID:25077176 ↗

BP4 The REVEL score is 0.435, which is above the ATM BP4 missense threshold of 0.249 or less, so missense computational evidence does not support BP4. SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, but this does not overcome the non-benign missense prediction under the ATM missense BP4 rule. Details ▾Hide ▴

Rule

Missense REVEL ≤0.249 and/or splice no-impact prediction SpliceAI ≤0.1, applied per ATM specification.

Evidence considered

REVEL 0.435.
SpliceAI max delta 0.01.
BayesDel 0.0616905.

Sources

cspec ↗revelspliceai ↗bayesdel

Not assessed · 3 · no assessment recorded

PS4 Published case reports and series were identified, but no qualifying variant-specific case-control result with p-value 0.05 or less and odds ratio, hazard ratio, or relative risk of at least 2, or lower 95% confidence interval of at least 1.5, was confirmed from the available evidence. Details ▾Hide ▴

Rule

Case-control studies; p-value ≤0.05 and effect estimate ≥2 or lower 95% CI ≥1.5.

Evidence considered

ATM PS4 requires qualifying case-control statistics.

Still missing

A qualifying variant-specific case-control analysis was not confirmed from the retrieved evidence.

Sources

cspec ↗PMID:20305132 ↗PMID:26898890 ↗

PP1 Affected family members with this variant were reported, but the available evidence does not provide sufficiently clear segregation counting under the ATM autosomal recessive PP1 framework to assign a PP1 strength level independently of PM3. Details ▾Hide ▴

Rule

AR condition: segregation in 1, 2, or at least 3 affected relatives for supporting, moderate, or strong.

Evidence considered

ATM PP1 for AR conditions requires defined affected-relative segregation counts.

Still missing

Detailed segregation counts and meioses suitable for ATM AR PP1 scoring were not confirmed from the retrieved evidence.

Sources

cspec ↗PMID:22345219 ↗

BP2 No unaffected adult individual with this variant observed in trans with a pathogenic or likely pathogenic ATM variant, and no qualifying benign co-occurrence evidence was identified. Details ▾Hide ▴

Rule

ATM BP2 point framework for unaffected non-A-T individuals.

Evidence considered

ATM BP2 requires point-based unaffected co-occurrence evidence.

Still missing

Phased co-occurrence data in unaffected adults were not identified.

Sources

cspec ↗vcep_atm_pm3_bp2_1_5

Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense variant and does not fall into the ATM or generic PVS1 null-variant categories such as nonsense, frameshift, canonical splice-site, initiation codon, or exon-level loss-of-function events. Details ▾Hide ▴

Rule

ATM PVS1 decision tree for loss-of-function variants only.

Evidence considered

PVS1 gene gate eligible for ATM loss of function.
Variant-level assessment states this variant is not in a default PVS1 null-variant bucket.

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_atm_pvs1_1_5

PS2 VCEPPS2 is not used for ATM under the ClinGen HBOP ATM specifications. Details ▾Hide ▴

VCEP rule

ATM VCEP: do not use PS2.

Evidence considered

ATM VCEP marks PS2 as not applicable.

Remaining individuals1 / 62,278	1.6e-05
European (non-Finnish)4 / 1,178,006	3.4e-06