ATM c.7031G>A, p.(Trp2344Ter)

Reasoning

NM_000051.3:c.7031G>A (NP_000042.3:p.(Trp2344Ter), p.(W2344*)) is a nonsense variant in exon 48 of the default ATM VCEP transcript. ATM loss of function is an established disease mechanism, and the ClinGen HBOP ATM VCEP v1.5 PVS1 specification applies to nonsense variants on NM_000051.3, treating all transcript exons as constitutive. The premature termination at residue 2344 is upstream of the VCEP's most 3' pathogenic C-terminal residue p.Arg3047 and is not an extreme 3' terminal truncation; therefore the VCEP caveat requiring caution for extreme 3' LOF variants does not trigger. The VCEP-specific null-variant path supports full-strength PVS1, with no named downgrade rule applicable. The Sun et al. Table S1 row independently identifies c.7031G>A as a high-confidence nonsense, non-functional variant, but this corroboration is not needed to assign the VCEP PVS1 strength. No variant-specific entry for c.7031G>A, p.Trp2344Ter, or p.W2344* was found in ATM_PVS1_1.5.pdf.txt; the call is based on the governing VCEP null-variant specification and the case consequence/transcript evidence.

Rule

ClinGen HBOP ATM VCEP v1.5 PVS1 null-variant path: nonsense variant on NM_000051.3 with established ATM loss-of-function mechanism; full strength because no named VCEP/SVI downgrade applies.

Evidence considered

• Case normalization identifies NM_000051.3:c.7031G>A as NP_000042.3:p.(Trp2344Ter), p.(W2344*), a nonsense variant.
• The ATM HBOP VCEP v1.5 PVS1 specification names NM_000051.3/ENST00000278616.8 as the default transcript and states that all exons are constitutive without major rescue isoforms.
• The ATM HBOP VCEP v1.5 specification states that the most 3' C-terminal residue considered pathogenic is p.Arg3047; p.Trp2344Ter is upstream of this boundary.
• The converted full-text Supplementary Table S1 row for c.7031G>A lists exon_48, Nonsense, W2344*, Combined_score -4.45490949255719, Non-functional, High, and DeepATM_predicted No.
• The generic PVS1 guidance in PMID:25741868 states that nonsense variants can disrupt gene function through absence of gene product or nonsense-mediated decay, while requiring attention to gene mechanism, transcript context, truncation position, and NMD; the ATM VCEP-specific specification governs this assessment.

Still missing

• No variant-specific entry for c.7031G>A, p.Trp2344Ter, or p.W2344* was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/ATM/fulltext/ATM_PVS1_1.5.pdf.txt.

Sources

Reasoning

The governing ATM VCEP v1.5 specifies PM2_Supporting at frequency <=0.001% in gnomAD v4, with one allele in a single subpopulation sufficient when n=1. gnomAD v4.1 reports total AF 0.0000619587% (1/1,613,978 alleles), highest subpopulation AF 0.001098% (1/91,074 South Asian alleles), and 0 homozygotes. The variant is also absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer records. The total AF is below the VCEP threshold and the single-observation subpopulation condition is satisfied, so PM2_Supporting is met.

Rule

Frequency <=0.001% in gnomAD v4 dataset; if n=1 in a single subpopulation, PM2_Supporting applies

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 specifies PM2_Supporting at frequency <=0.001% in gnomAD v4 and states that n=1 in a single subpopulation is sufficient.
• gnomAD v4.1 reports total AF 6.195871319187746e-07 (0.0000619587%), 1/1,613,978 alleles, highest South Asian AF 1.098008213101434e-05 (0.001098%) from 1/91,074 alleles, and 0 homozygotes.
• The variant is absent from the available gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer records; v3.1 non-cancer is a genomes-only source.

Sources

Reasoning

The ATM VCEP v1.5 PM5 rule is gene-specific and differs from the classic same-residue missense PM5 use: it applies at Supporting strength to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This variant is a truncating nonsense change terminating at p.Trp2344, which is upstream of p.Arg3047, so the specified PM5 Supporting rule is met. The absence of classic same-residue missense candidates does not prevent application because the governing VCEP rule explicitly defines this truncation-cutoff path.

Rule

ATM VCEP v1.5 PM5 Supporting: apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.

Evidence considered

• The ATM VCEP PM5 rule specifies Supporting strength for frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.
• The case variant is a nonsense truncation at p.Trp2344, and residue 2344 is upstream of residue 3047.
• The collected PM5 candidate artifact correctly identifies the governing ATM mode as truncation_cutoff_gene_specific and instructs review against the governing PM5 rule rather than classic missense PM5.

Sources

Reasoning

The governing ATM VCEP v1.5 (ClinGen HBOP) defines PS4 at Pathogenic Strong as: "Case-control studies; p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=2 OR lower 95% CI >=1.5)." The comparison operator for the enrichment statistic, quoted literally from that rule, is ">=" (greater-than-or-equal), and this criterion strengthens as the value goes UP: met requires OR/HR/RR >= 2, or lower 95% CI >= 1.5, together with p <= .05. Explicit substitution: no odds ratio, hazard ratio, relative risk, p-value, or confidence interval for ATM c.7031G>A (p.Trp2344Ter) is reported anywhere in the retrieved evidence, so no inequality of the form "value >= 2" can even be written; with no value to substitute, neither "OR >= 2" nor "lower 95% CI >= 1.5" is satisfied, and PS4 is not met. The four PS4/PP5 candidate publications that were retrievable (PMID:25394175, PMID:24366376, PMID:25741868, PMID:27413114) contain no ATM c.7031G>A content and no case-control enrichment data; the remaining leads (PMID:26389210, PMID:31479213, PMID:34012068) had no retrievable full text. Frequency data alone (gnomAD v4.1 total AF 6.195871319187746e-07, 1/1,613,978 alleles, 0 homozygotes) describe rarity, not case-control enrichment, and cannot be converted into PS4 under this specification.

Rule

Case-control studies; p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=2 OR lower 95% CI >=1.5).

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 (cspec) sets PS4 at Pathogenic Strong with the rule: "Case-control studies; p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=2 OR lower 95% CI >=1.5)."
• Operator and direction taken only from that PS4 rule, not from any other criterion in this group: ">=" for OR/HR/RR and ">= 1.5" for the lower 95% CI, i.e. larger values strengthen PS4; met requires value >= 2 (OR/HR/RR) or value >= 1.5 (lower 95% CI).
• No odds ratio, hazard ratio, relative risk, p-value, or confidence interval for ATM c.7031G>A appears in any retrieved source, so the required comparison is unformable and PS4 cannot be met.
• The variant is a rare truncating allele: gnomAD v4.1 total AF 6.195871319187746e-07 (1/1,613,978 alleles, 0 homozygotes), highest subpopulation AF 1.098008213101434e-05 (1/91,074 South Asian alleles), absent from gnomAD v2.1; rarity is not case-control enrichment evidence.
• PMID:25394175 (ACMG/NSGC referral-indications guideline) was screened in full text and does not mention ATM, c.7031G>A, or p.(Trp2344Ter); it reports no enrichment statistic.
• PMID:24366376 (USPSTF BRCA-related cancer risk assessment) was screened in full text and discusses only BRCA1/BRCA2; it contains no ATM or c.7031G>A content and no case-control data.
• PMID:25741868 (ACMG/AMP 2015 standards) was consulted for the general PS4 case-control definition; it reports no ATM-specific cohort or variant-level statistics.
• ClinVar variation 2679782 labels the variant Pathogenic on laboratory submissions only (4 clinical laboratories Pathogenic, 1 Likely pathogenic); that aggregate label is a classification, not case-control enrichment evidence.

Still missing

• No case-control study reporting an odds ratio, hazard ratio, relative risk, or confidence interval for ATM c.7031G>A was identified in this case.
• PMID:26389210, PMID:31479213 and PMID:34012068 were triaged as PS4 candidate leads but no full text was retrievable, so their content could not be screened.

Sources

Reasoning

The ATM VCEP v1.5 lists PP5 as Not Applicable, but the governing policy for this criterion is applied globally and ignores that NA flag: PP5 may only be triggered by an exact-variant ClinVar classification from an expert panel, with Pathogenic or Likely pathogenic supporting PP5 at supporting strength. ClinVar variation 2679782 (ATM NM_000051.4:c.7031G>A, p.Trp2344Ter) has review status "criteria provided, single submitter" and zero expert-panel submissions; all five submissions are ordinary laboratory submissions (4 clinical laboratories reporting Pathogenic, 1 reporting Likely pathogenic). No ClinGen/VCEP expert panel or equivalent expert assertion exists for this exact variant, so the sole condition for PP5 is not satisfied and PP5 is not met. Laboratory-level classifications and the aggregate ClinVar label were deliberately not treated as triggering evidence. No numeric threshold is defined for PP5 by this specification, so no threshold-direction comparison applies.

Rule

PP5 is Not Applicable under the ATM VCEP v1.5 specification; evaluated under the global policy requiring an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification (supporting strength).

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 (cspec) lists PP5 as Not Applicable.
• Global policy applied for PP5: only an exact-variant ClinVar expert-panel classification triggers the criterion, with Pathogenic/Likely pathogenic supporting PP5 at supporting strength; ordinary laboratory submissions, aggregate ClinVar labels and non-expert assertions must never trigger it.
• ClinVar variation 2679782 has review status "criteria provided, single submitter" and 0 expert-panel submissions (expert_panels empty); submissions are 4 clinical laboratories Pathogenic and 1 clinical laboratory Likely pathogenic.
• PMID:25394175 and PMID:24366376 were the PP5 candidate leads carried by the ClinVar submissions; both were screened and contain no ATM or c.7031G>A content, and neither is an expert-panel assertion.
• PMID:26389210 was also triaged as a PP5 lead but no full text or abstract was retrievable, so it contributed no expert-panel classification.

Still missing

• PP5 could only become applicable if a ClinGen expert panel (e.g. the ATM VCEP) submitted an exact-variant classification to ClinVar for this variant; no such assertion currently exists.

Sources

Reasoning

The governing ATM VCEP v1.5 specifies BA1 at grpmax filtering AF >0.5% in gnomAD v4. The variant's gnomAD v4.1 total AF is 6.195871319187746e-07 (0.0000619587%), with 1 of 1,613,978 alleles and no homozygotes; this is far below the VCEP threshold, so BA1 is not met.

Rule

Grpmax Filtering AF >0.5% in gnomAD v4 dataset

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 specifies BA1 as grpmax filtering AF >0.5% in gnomAD v4.
• gnomAD v4.1 reports total AF 6.195871319187746e-07, equivalent to 0.0000619587%, from 1/1,613,978 alleles, with 0 homozygotes.
• The available non-cancer gnomAD v2.1 and v3.1 records are absent; neither could support BA1 because the observed frequency is already far below the governing threshold.

Sources

Reasoning

The governing ATM VCEP v1.5 specifies BS1 at grpmax filtering AF >0.05% in gnomAD v4. The variant's gnomAD v4.1 total AF is 6.195871319187746e-07 (0.0000619587%), and its highest reported subpopulation AF is 1.098008213101434e-05 (0.001098%), both below 0.05%; therefore BS1 is not met.

Rule

Grpmax Filtering AF >0.05% in gnomAD v4 dataset

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 specifies BS1 as grpmax filtering AF >0.05% in gnomAD v4.
• gnomAD v4.1 reports total AF 6.195871319187746e-07 (0.0000619587%) and highest observed subpopulation AF 1.098008213101434e-05 (0.001098%) in South Asian individuals, with 0 homozygotes.
• The available non-cancer gnomAD v2.1 and v3.1 records are absent; neither could support BS1 because the observed frequency remains below the governing threshold.

Sources

Reasoning

The ATM VCEP framework uses BS3_Supporting when a variant rescues either an ATM-specific feature or radiosensitivity, and BS3_Moderate when it rescues both. The governing Table S1 entry for c.7031G>A (p.W2344*) reports a direct-measurement classification of Non-functional with High confidence and DeepATM_predicted=No, which is incompatible with a normal functional rescue result. The result is from an assay outside the VCEP-approved calibration set, so it should not be converted into an additional calibrated benign strength; human review remains appropriate because this is the only variant-specific functional result available.

Rule

ATM VCEP v1.5 BS3: Supporting for rescue of either an ATM-specific feature or radiosensitivity; Moderate for rescue of both.

Evidence considered

• ATM VCEP v1.5 defines BS3_Supporting as rescue of either an ATM-specific feature or radiosensitivity, and BS3_Moderate as rescue of both.
• Suppl_TableS1_PMID 40580951.xlsx.txt row 22491 records c.7031G>A / W2344* as Non-functional with High confidence and DeepATM_predicted=No, indicating direct measurement rather than model-only prediction.
• Because the direct measurement is non-functional and the assay is not one of the VCEP-calibrated approved assays, it does not support BS3 and should not be assigned a VCEP-calibrated benign strength without human review.

Still missing

• The variant was not found under c.7031G>A, p.Trp2344Ter, or p.W2344* in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx.txt; that file reports assay methodology and calibration, not variant-specific results.
• The variant was not found under p.Trp2344Ter or p.W2344* in Suppl_TableS1_PMID 40580951.xlsx.txt, but it was found under c.7031G>A at converted-text row 22491.
• No variant-specific normal-rescue result was found in the approved ATM kinase-activity papers PMID:18634022, PMID:19431188, or PMID:11805335.

Sources

Reasoning

The ATM VCEP v1.5 lists BP6 as Not Applicable, but the governing policy for this criterion is applied globally and ignores that NA flag: BP6 may only be triggered by an exact-variant ClinVar classification from an expert panel, with Benign or Likely benign supporting BP6 at supporting strength. ClinVar variation 2679782 (ATM NM_000051.4:c.7031G>A, p.Trp2344Ter) has review status "criteria provided, single submitter" and zero expert-panel submissions; there is no benign or likely benign expert assertion for this exact variant, and the only submissions present are laboratory-level pathogenic-direction classifications (4 Pathogenic, 1 Likely pathogenic). The sole condition for BP6 is therefore not satisfied and BP6 is not met. The aggregate ClinVar label and ordinary laboratory submissions were deliberately not treated as triggering evidence. No numeric threshold is defined for BP6 by this specification, so no threshold-direction comparison applies.

Rule

BP6 is Not Applicable under the ATM VCEP v1.5 specification; evaluated under the global policy requiring an exact-variant ClinVar expert-panel Benign/Likely benign classification (supporting strength).

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 (cspec) lists BP6 as Not Applicable.
• Global policy applied for BP6: only an exact-variant ClinVar expert-panel classification triggers the criterion, with Benign/Likely benign supporting BP6 at supporting strength; ordinary laboratory submissions, aggregate ClinVar labels and non-expert assertions must never trigger it.
• ClinVar variation 2679782 has review status "criteria provided, single submitter" and 0 expert-panel submissions (expert_panels empty); the recorded submissions are 4 clinical laboratories Pathogenic and 1 clinical laboratory Likely pathogenic, with no benign-direction submission.
• The ClinVar-linked publications screened for this criterion (PMID:25394175, PMID:24366376) contain no ATM or c.7031G>A content and include no benign assertion.

Still missing

• BP6 could only become applicable if a ClinGen expert panel (e.g. the ATM VCEP) submitted an exact-variant Benign/Likely benign classification to ClinVar for this variant; no such assertion currently exists.

Sources

Reasoning

The ATM VCEP framework permits PS3_Supporting when a variant fails an ATM-specific feature and PS3_Moderate only when it fails both an ATM-specific feature and radiosensitivity; strong PS3 is explicitly disallowed. The governing Sun et al. Table S1 entry for NM_000051.3:c.7031G>A (p.W2344*) reports Classification=Non-functional, Confidence=High, and DeepATM_predicted=No, indicating a direct prime-editing functional measurement rather than a computational extrapolation. However, the assay is not one of the three functional assay systems calibrated in the current ATM VCEP PS3/BS3 specification, and the table entry does not provide the VCEP-required ATM-specific readout and radiosensitivity combination needed to assign Supporting versus Moderate. Therefore the result supports loss of function but cannot be assigned a VCEP PS3 strength without human review.

Rule

ATM VCEP v1.5 PS3: Supporting for failure of an ATM-specific feature only; Moderate for failure of both an ATM-specific feature and radiosensitivity; do not use Strong.

Evidence considered

• ATM VCEP v1.5 specifies PS3_Supporting for failure of an ATM-specific feature, PS3_Moderate for failure of both an ATM-specific feature and radiosensitivity, and states not to use PS3 as strong.
• Suppl_TableS1_PMID 40580951.xlsx.txt row 22491 records c.7031G>A / W2344* as Nonsense with Classification=Non-functional, Confidence=High, and DeepATM_predicted=No; the VCEP instructions define DeepATM_predicted=No as a direct prime-editing functional measurement.
• The governing VCEP materials state that the Sun et al. assay is not among the three currently calibrated ATM PS3/BS3 assays and requires human review when it is the only PS3/BS3 evidence.

Still missing

• The variant was not found under c.7031G>A, p.Trp2344Ter, or p.W2344* in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx.txt; that file is a methodology and strength-calibration table, not a per-variant results table.
• The variant was not found under p.Trp2344Ter or p.W2344* in Suppl_TableS1_PMID 40580951.xlsx.txt, but it was found under c.7031G>A at converted-text row 22491.
• No variant-specific result was found in the approved ATM kinase-activity papers PMID:18634022, PMID:19431188, or PMID:11805335; the available Table S1 result does not report the VCEP-calibrated ATM-specific readout or radiosensitivity result.

Sources

Reasoning

The governing ClinGen HBOP ATM VCEP v1.5 PM3/BP2 specification requires scored observations in unrelated A-T probands, with phenotype classified as confident or consistent and phase established as confirmed in trans, phase unknown, second variant unidentified/VUS, or homozygous. The available case evidence contains no affected A-T proband observation, no co-occurring pathogenic or likely pathogenic ATM variant, and no phase or homozygosity information for NM_000051.3:c.7031G>A (NP_000042.3:p.(Trp2344Ter), p.(W2344*)). The variant is rare in gnomAD v4.1 (1/1,613,978 alleles; homozygotes 0), so the VCEP rarity prerequisite is satisfied, but no PM3 points can be assigned. The governing file ATM_PM3_BP2_1.5.pdf was searched under c.7031G>A, p.Trp2344Ter, and p.W2344*; it contains no variant-specific entry, only the general scoring table.

Rule

PM3_VeryStrong >= 8 points; PM3_Strong = 4 points; PM3 = 2 points; PM3_Supporting = 1 point, using the ATM PM3/BP2 points table.

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 assigns PM3 points only from unrelated A-T probands: 4.0/2.0/1.0/2.0 points for a confident phenotype depending on confirmed trans, phase unknown, second variant unidentified or VUS, or homozygosity; consistent phenotypes receive half those values.
• The case evidence documents NM_000051.3:c.7031G>A as rare in gnomAD v4.1 at 1/1,613,978 alleles with zero homozygotes, satisfying the VCEP rarity prerequisite but providing no affected-proband or phase evidence.
• The case evidence contains no documented A-T-affected proband, pathogenic or likely pathogenic ATM variant in trans, or parental/other phase result for this variant.
• ATM_PM3_BP2_1.5.pdf was searched for c.7031G>A, p.Trp2344Ter, and p.W2344*; no variant-specific entry was found.

Still missing

• No affected A-T proband observation with a confident or consistent phenotype is available.
• No co-occurring pathogenic or likely pathogenic ATM variant is documented.
• No parental or other testing establishes confirmed in-trans phase, phase unknown, homozygosity, or cis configuration.
• No entry for c.7031G>A, p.Trp2344Ter, or p.W2344* was found when ATM_PM3_BP2_1.5.pdf was searched; the file provides a general PM3/BP2 scoring table rather than variant-specific rows.

Sources

Reasoning

The ClinGen HBOP ATM VCEP version 1.5 provides a PP1 rule only for the autosomal recessive condition, assigning supporting strength for segregation in one affected relative, moderate strength for two affected relatives, and strong strength for at least three affected relatives. The available case evidence contains no documented affected relatives, parental testing, informative meioses, segregation results, or non-segregation results for NM_000051.3:c.7031G>A, so no PP1 strength can be assigned.

Rule

For ATM autosomal recessive disease, PP1 supporting requires segregation in 1 affected relative; moderate requires 2 affected relatives; strong requires at least 3 affected relatives.

Evidence considered

• The ATM VCEP version 1.5 PP1 rule assigns supporting strength for segregation in 1 affected relative, moderate strength for 2 affected relatives, and strong strength for at least 3 affected relatives in the autosomal recessive condition.
• The case materials provide no variant-specific family segregation, parental testing, affected-relative count, meiosis count, or non-segregation evidence.

Still missing

• Documented segregation data are needed, including the number and phenotype of affected relatives, variant genotypes, and informative meioses.
• Parental and other family testing results are not available to evaluate phase or non-segregation.

Sources

Reasoning

The governing ClinGen HBOP ATM VCEP v1.5 BP2 specification requires scored observations in unaffected non-A-T adults older than 18 years who carry the variant with a pathogenic or likely pathogenic ATM variant in trans, with separate point values for confirmed trans, phase unknown, or homozygosity and laboratory/database settings. The available case evidence contains no unaffected adult observation, no co-occurring pathogenic or likely pathogenic ATM variant, and no phase or homozygosity information for NM_000051.3:c.7031G>A (NP_000042.3:p.(Trp2344Ter), p.(W2344*)). Therefore no BP2 points can be assigned. The variant is rare in gnomAD v4.1 (1/1,613,978 alleles; homozygotes 0), but this population observation is not an eligible phenotyped unaffected-adult BP2 observation under the VCEP. The governing file ATM_PM3_BP2_1.5.pdf was searched under c.7031G>A, p.Trp2344Ter, and p.W2344*; it contains no variant-specific entry, only the general scoring table.

Rule

BP2_Strong <= -4 points; BP2_Moderate = -2 points; BP2_Supporting = -1 point, using the ATM PM3/BP2 points table.

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 assigns BP2 points only for unaffected non-A-T adults older than 18 years carrying the variant with a pathogenic or likely pathogenic ATM variant, with -4.0 for confirmed trans, -2.0 for phase unknown, and laboratory/database homozygous values of -2.0/-1.0.
• The case evidence documents NM_000051.3:c.7031G>A as rare in gnomAD v4.1 at 1/1,613,978 alleles with zero homozygotes, but this is not a phenotyped adult observation eligible for BP2.
• The case evidence contains no unaffected adult observation, co-occurring pathogenic or likely pathogenic ATM variant, or phase result for this variant.
• ATM_PM3_BP2_1.5.pdf was searched for c.7031G>A, p.Trp2344Ter, and p.W2344*; no variant-specific entry was found.

Still missing

• No unaffected non-A-T adult older than 18 years carrying the variant is documented.
• No co-occurring pathogenic or likely pathogenic ATM variant is documented in such an individual.
• No confirmed-trans, phase-unknown, laboratory-setting, database-setting, or homozygous BP2 observation is documented.
• The gnomAD v4.1 observation is a population-frequency observation, not an eligible phenotyped unaffected-adult BP2 observation under the VCEP.
• No entry for c.7031G>A, p.Trp2344Ter, or p.W2344* was found when ATM_PM3_BP2_1.5.pdf was searched; the file provides a general PM3/BP2 scoring table rather than variant-specific rows.

Sources