ATM c.3285-15C>T, p.?

Reasoning

BP4 is evaluated on the SpliceAI path because NM_000051.4:c.3285-15C>T is intronic/splice-region and has NP_000042.3:p.?. The maximum SpliceAI delta is 0.01, which meets the ATM VCEP Version 1.6 BP4 splicing threshold of <=0.1; BP4 Supporting is therefore met. The governing ATM Suppl_TableS1_PMID 40580951.xlsx table was searched for c.3285-15C>T and p.?; no pre-assigned BP4 entry for this variant was found.

Rule

ATM VCEP Version 1.6 BP4 Splicing: no predicted impact via splicing (SpliceAI <=0.1).

Evidence considered

• The normalized variant is NM_000051.4:c.3285-15C>T with predicted protein consequence NP_000042.3:p.?; this is an intronic splice-region variant, so SpliceAI rather than REVEL is the applicable computational path.
• SpliceAI reports a maximum delta score of 0.01.
• The ATM VCEP Version 1.6 specification assigns BP4 Supporting for no predicted splicing impact at SpliceAI <=0.1; the observed maximum delta of 0.01 meets that threshold.
• The generic SpliceAI supporting threshold is also <=0.1, from Jaganathan et al. 2019 (PMID:30661751).

Still missing

• No entry for c.3285-15C>T or p.? was found when searching Suppl_TableS1_PMID 40580951.xlsx; therefore no pre-assigned BP4 code was available from that governing table.

Sources

Reasoning

NM_000051.4:c.3285-15C>T is an intronic splice-region variant outside the canonical +/-1,2 positions and is annotated as NP_000042.3:p.?. The ATM VCEP PVS1 guide defines PVS1 for null variants including canonical +/-1,2 splice variants, but this variant is not in that null-variant category; SpliceAI predicts no significant splice impact with a maximum delta of 0.01, below the VCEP splice-impact threshold of 0.2 for PP3. No RNA evidence establishes an aberrant transcript or loss of function. The exact variant notation c.3285-15C>T and protein notation p.? were searched in ATM_PVS1_1.5.pdf, with no variant-specific entry found.

Rule

ATM_PVS1_1.5.pdf PVS1 null-variant definition and decision guide

Evidence considered

• The ATM_PVS1_1.5.pdf guide defines PVS1 for null variants, including canonical +/-1,2 splice sites, and cautions that splice variants predicted to cause exon skipping require specific consideration.
• The case is NM_000051.4:c.3285-15C>T with protein annotation NP_000042.3:p.?; the variant is intronic and not a canonical +/-1,2 splice-site change.
• SpliceAI reports DS_AG 0.004, DS_AL 0.01, DS_DG 0.004, DS_DL 0.0, with maximum delta 0.01; the ATM VCEP splice-impact threshold is >=0.2 for PP3.
• No RNA evidence establishing aberrant splicing or loss of function is available.
• The exact notations c.3285-15C>T and p.? were searched in ATM_PVS1_1.5.pdf and no variant-specific entry was found.

Still missing

• No exact c.3285-15C>T or p.? entry was found in ATM_PVS1_1.5.pdf.
• No RNA study demonstrating aberrant splicing or transcript loss was available.

Sources

Reasoning

The governing ATM VCEP v1.6 specifies PM2 Supporting when the frequency is at most 0.001% in the gnomAD subpopulation with the highest frequency, with an exception for a single observation confined to one subpopulation. The highest all-comers subpopulation frequency is 0.0409475% (13/31,748 alleles) in gnomAD v2.1 Admixed American and 0.0334784% (2/5,974 alleles) in gnomAD v4.1 Middle Eastern, both above 0.001%; neither meets the single-observation exception. Therefore PM2 is not met.

Rule

ATM VCEP v1.6: PM2 Supporting at frequency <=0.001% in the highest-frequency gnomAD subpopulation; exception only when n=1 in one subpopulation and absent from all others.

Evidence considered

• ATM VCEP version 1.6 defines PM2 Supporting as frequency <=0.001% in the gnomAD subpopulation with the highest frequency; a single observation confined to one subpopulation is an exception.
• All-comers gnomAD v2.1 has the highest observed subpopulation AF of 0.0004094746 (0.0409475%), Admixed American, based on 13/31,748 alleles.
• All-comers gnomAD v4.1 has the highest observed subpopulation AF of 0.000334784 (0.0334784%), Middle Eastern, based on 2/5,974 alleles; this is not a single-observation exception.
• The non-cancer datasets do not provide a basis to apply PM2: gnomAD v2.1 non-cancer exome AF is 0.00641589% and gnomAD v3.1 non-cancer's highest subpopulation AF is 0.0507099%, both above 0.001%.

Sources

Reasoning

PP3 is evaluated on the SpliceAI path because NM_000051.4:c.3285-15C>T is an intronic splice-region variant with NP_000042.3:p.? and no protein-length-changing consequence. The case SpliceAI result has a maximum delta score of 0.01, below the ATM VCEP Version 1.6 splicing PP3 threshold of >=0.2, so PP3 is not met. The governing ATM Suppl_TableS1_PMID 40580951.xlsx table was searched for c.3285-15C>T and p.?; no pre-assigned PP3 or BP4 entry for this variant was found.

Rule

ATM VCEP Version 1.6 PP3 Splicing: predicted impact via splicing (SpliceAI >=0.2) for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.

Evidence considered

• The normalized variant is NM_000051.4:c.3285-15C>T with predicted protein consequence NP_000042.3:p.?; this is an intronic splice-region variant, so SpliceAI rather than REVEL is the applicable computational path.
• SpliceAI reports DS_AG 0.004, DS_AL 0.01, DS_DG 0.004, and DS_DL 0.0; the maximum delta is 0.01.
• The ATM VCEP Version 1.6 specification assigns PP3 Supporting for predicted splicing impact at SpliceAI >=0.2; the observed maximum delta of 0.01 does not meet that threshold.
• The generic SpliceAI supporting threshold is also >=0.2, from Jaganathan et al. 2019 (PMID:30661751).

Still missing

• No entry for c.3285-15C>T or p.? was found when searching Suppl_TableS1_PMID 40580951.xlsx; therefore no pre-assigned PP3 code was available from that governing table.

Sources

Reasoning

The governing ATM VCEP v1.6 specifies BA1 when the gnomAD grpmax filtering allele frequency is greater than 0.5%. The variant's all-comers gnomAD grpmax FAF is 0.00022392 (0.022392%) in v2.1 and 0.00017606 (0.017606%) in v4.1, both below the >0.5% threshold. The available non-cancer datasets also do not approach the threshold: gnomAD v2.1 non-cancer exomes have AF 0.0000641589, and gnomAD v3.1 non-cancer has AF 0.0000206751. Therefore BA1 is not met.

Rule

ATM VCEP v1.6: BA1 when grpmax filtering AF >0.5% in gnomAD.

Evidence considered

• ATM VCEP version 1.6 defines BA1 as grpmax filtering AF >0.5% in gnomAD.
• All-comers gnomAD v2.1 reports grpmax FAF 0.00022392 (0.022392%), and gnomAD v4.1 reports grpmax FAF 0.00017606 (0.017606%), both below the VCEP threshold.
• The non-cancer datasets are also far below the BA1 threshold: gnomAD v2.1 non-cancer exomes AF 0.0000641589 and gnomAD v3.1 non-cancer AF 0.0000206751.

Sources

Reasoning

The governing ATM VCEP v1.6 specifies BS1 when the gnomAD grpmax filtering allele frequency is greater than 0.05%. The all-comers grpmax FAF is 0.00022392 (0.022392%) in v2.1 and 0.00017606 (0.017606%) in v4.1, both below 0.05%. The non-cancer datasets likewise remain below this threshold, with v2.1 non-cancer exome AF 0.0000641589 and v3.1 non-cancer AF 0.0000206751. Therefore BS1 is not met.

Rule

ATM VCEP v1.6: BS1 when grpmax filtering AF >0.05% in gnomAD.

Evidence considered

• ATM VCEP version 1.6 defines BS1 as grpmax filtering AF >0.05% in gnomAD.
• All-comers gnomAD v2.1 grpmax FAF is 0.00022392 (0.022392%) and v4.1 grpmax FAF is 0.00017606 (0.017606%), both below the VCEP threshold.
• The non-cancer datasets are below the BS1 threshold: gnomAD v2.1 non-cancer exome AF 0.0000641589 and gnomAD v3.1 non-cancer AF 0.0000206751.

Sources

Reasoning

The ATM VCEP PS1 splicing pathway requires a known pathogenic or likely pathogenic reference variant with the same predicted splice event and a directly comparable position. Searches of ATM_PS1_1.5.pdf and ATM_PS1_1.6.pdf found no entry for c.3285-15C>T or p.?, and the case has no qualifying reference splice variant. SpliceAI max delta is 0.01, below the VCEP PP3 splice threshold of 0.2, so the required damaging baseline splice evidence is also unavailable. PS1 cannot be assigned, but the absence of a table entry is not evidence that the criterion is definitively not met.

Rule

Use the ATM PS1 Splicing table only when a qualifying pathogenic or likely pathogenic reference variant has the same predicted splice event and the VUA prediction is of similar or greater strength.

Evidence considered

• ATM PS1 requires the VUA's predicted splice event to precisely match that of a known pathogenic or likely pathogenic reference variant, with prediction strength at least as strong.
• The searched ATM PS1 v1.5 and v1.6 full-text files contain no entry for c.3285-15C>T or p.?.
• The case variant is intronic with protein consequence p.? and SpliceAI max delta 0.01, below the ATM VCEP splice PP3 threshold of 0.2.

Still missing

• No c.3285-15C>T or p.? entry was found in ATM_PS1_1.5.pdf.
• No c.3285-15C>T or p.? entry was found in ATM_PS1_1.6.pdf.
• No qualifying pathogenic or likely pathogenic reference variant with the same predicted splice event and comparable position was identified.

Sources

Reasoning

The ATM VCEP v1.6 specification permits PS3 only for variant-specific damaging functional evidence: supporting when an ATM-specific feature such as phosphorylation fails, and moderate only when both an ATM-specific feature and radiosensitivity fail; strong is not permitted. The governing approved-assay table is a methodology and calibration table, not a per-variant results table, and its three kinase-assay papers (PMID:18634022, PMID:19431188, and PMID:11805335) and approved radiosensitivity assay require confirmation that this exact variant was tested. The exact notations NM_000051.4:c.3285-15C>T, c.3285-15C>T, and NP_000042.3:p.? were searched in the full text of clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx and Suppl_TableS1_PMID 40580951.xlsx; neither governing file contained an exact variant result. The case evidence bundle and paper extracts likewise contain no variant-specific functional assay result. Therefore PS3 cannot be assigned from the available evidence.

Rule

Do not use as strong. Use when a variant fails to rescue both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. Use when a variant fails to rescue an ATM specific feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency.

Evidence considered

• ATM VCEP v1.6 PS3 rule: do not use PS3 as strong; use PS3_Moderate when both an ATM-specific feature and radiosensitivity fail, and PS3_Supporting when an ATM-specific feature alone fails; radiosensitivity alone receives no weight.
• The approved assay table describes ATM kinase activity assays using stable ATM cDNA transfection into ATM-null lymphoblastoid cells with phosphorylation readouts and calibrates them at PS3_Supporting, but it explicitly does not report which variants were tested.
• The approved assay table describes Mitui 2009 radiosensitivity calibration at PS3_Moderate only when combined with qualifying kinase-activity evidence; no exact current-variant result is present.
• Searches of both governing VCEP full-text files for c.3285-15C>T, c.3285-15, and p.? returned no exact variant entry or functional readout.

Still missing

• No exact entry for NM_000051.4:c.3285-15C>T, c.3285-15C>T, or NP_000042.3:p.? was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; this file is a calibration/methodology table rather than a per-variant results table.
• No exact entry for NM_000051.4:c.3285-15C>T, c.3285-15C>T, or NP_000042.3:p.? was found in Suppl_TableS1_PMID 40580951.xlsx.
• The primary approved assay papers (PMID:18634022, PMID:19431188, and PMID:11805335) were not available as variant-specific extracted case evidence, so exact testing and readouts for this variant could not be verified.

Sources

Reasoning

The ATM ClinGen HBOP VCEP version 1.6 makes PS4 applicable at Strong strength only for case-control studies with p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥2 or lower 95% confidence interval ≥1.5). No case-control counts, p-value, odds ratio, hazard ratio, relative risk, confidence interval, or validated variant-specific phenotype-enrichment study was identified for NM_000051.4:c.3285-15C>T. The reviewed ClinVar-linked publications do not report this exact variant or ATM-specific case-control evidence, so PS4 cannot be adjudicated.

Rule

ATM HBOP VCEP v1.6 PS4 Strong: case-control studies; p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥2 or lower 95% CI ≥1.5).

Evidence considered

• The governing ATM VCEP v1.6 PS4 rule states: "Case-control studies; p-value ≤.05 and (Odds ratio, hazard ratio, or relative risk ≥2 or lower 95% CI ≥1.5)."
• The exact variant NM_000051.4:c.3285-15C>T is not reported in the reviewed ClinVar-linked publications, and no case-control effect estimate or p-value for this variant was found.
• No numeric PS4 comparison can be written because no qualifying p-value, effect estimate, or confidence interval is available.

Still missing

• A variant-specific ATM case-control study or equivalent validated phenotype-enrichment dataset with p-value and effect estimate is unavailable.

Sources

Reasoning

The ATM VCEP PM3 framework assigns points only for unrelated A-T-affected probands carrying the variant with a sufficiently rare allele and evidence of homozygosity, a pathogenic/likely pathogenic variant in trans, or phase-unknown/second-variant observations. The case evidence contains no affected-proband observation, A-T phenotype, homozygous patient, co-occurring pathogenic or likely pathogenic ATM variant, parental phase result, or other inheritance evidence for NM_000051.4:c.3285-15C>T (NP_000042.3:p.?). The governing file ATM_PM3_BP2_1.5.pdf was searched for c.3285-15C>T and p.? and contains no variant-specific entry; therefore no PM3 points or strength can be assigned. The variant is sufficiently rare for the VCEP prerequisite in gnomAD v4.1 (grpmax FAF 0.00017606), but rarity alone does not establish PM3.

Rule

ATM VCEP PM3: assign points from unrelated A-T probands; PM3 Supporting=1.0, Moderate=2.0, Strong=4.0, Very Strong=8.0 points.

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 requires PM3 points from unrelated A-T probands and assigns 4.0, 2.0, 1.0, or 2.0 points for a confident phenotype depending on confirmed trans, phase unknown, an unidentified/VUS second variant, or homozygosity; consistent-phenotype values are half those amounts.
• The same VCEP table converts total PM3 points to Supporting at 1.0, Moderate at 2.0, Strong at 4.0, and Very Strong at 8.0 points.
• The consolidated allelic evidence contained no affected-proband, A-T phenotype, homozygous, pathogenic-in-trans, or phase observation for NM_000051.4:c.3285-15C>T.
• Direct search of ATM_PM3_BP2_1.5.pdf for c.3285-15C>T and p.? found no variant-specific entry.
• gnomAD v4.1 reports grpmax FAF 0.00017606, satisfying the VCEP rarity prerequisite but providing no PM3 observation or phase information.

Still missing

• No affected A-T proband observation with a documented confident or consistent phenotype.
• No documented homozygous observation or co-occurring pathogenic/likely pathogenic ATM variant.
• No parental or other phase evidence establishing trans or phase-unknown status.
• No entry for c.3285-15C>T or p.? was found when ATM_PM3_BP2_1.5.pdf was searched.

Sources

Reasoning

The ATM VCEP specifies PP1 for the autosomal-recessive condition as Supporting with segregation in 1 affected relative, Moderate with 2 affected relatives, and Strong with at least 3 affected relatives. The available case evidence reports no affected relatives, informative meioses, family segregation, or variant-positive/variant-negative relatives for NM_000051.4:c.3285-15C>T. PP1 therefore cannot be assigned.

Rule

ClinGen HBOP ATM VCEP v1.6 PP1: autosomal-recessive condition; Supporting for segregation in 1 affected relative, Moderate for 2, Strong for at least 3

Evidence considered

• The ATM VCEP PP1 rule assigns Supporting for segregation in 1 affected relative, Moderate for 2 affected relatives, and Strong for at least 3 affected relatives in the autosomal-recessive condition.
• No affected-relative segregation, parental testing, informative meioses, or non-segregation observations for this variant are documented in the available case evidence.

Still missing

• Documented affected relatives carrying the variant and their phenotypes
• Informative family genotypes and phase
• Number of informative meioses and any non-segregating relatives

Sources

Reasoning

The ATM VCEP v1.6 specification permits BS3 at supporting strength when a variant rescues either an ATM-specific feature or radiosensitivity, and at moderate strength when it rescues both; the governing approved-assay table calibrates assay methodology but is not a per-variant results table. The exact notations NM_000051.4:c.3285-15C>T, c.3285-15C>T, and NP_000042.3:p.? were searched in the full text of clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx and Suppl_TableS1_PMID 40580951.xlsx; neither governing file contained an exact variant result. The case evidence bundle and paper extracts contain no variant-specific rescue result with assay controls and readout values. Therefore BS3 cannot be assigned from the available evidence.

Rule

Use when a variant rescues both an ATM specific feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. Use when a variant rescues EITHER an ATM specific feature OR rescues radiosensitivity.

Evidence considered

• ATM VCEP v1.6 BS3 rule: use BS3_Supporting when a variant rescues either an ATM-specific feature or radiosensitivity, and BS3_Moderate when it rescues both.
• The approved assay table documents positive and negative controls and normal/abnormal assay thresholds for ATM kinase activity and radiosensitivity, but it explicitly does not report which variants were tested.
• Searches of both governing VCEP full-text files for c.3285-15C>T, c.3285-15, and p.? returned no exact variant entry or rescue readout.

Still missing

• No exact entry for NM_000051.4:c.3285-15C>T, c.3285-15C>T, or NP_000042.3:p.? was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; this file is a calibration/methodology table rather than a per-variant results table.
• No exact entry for NM_000051.4:c.3285-15C>T, c.3285-15C>T, or NP_000042.3:p.? was found in Suppl_TableS1_PMID 40580951.xlsx.
• No variant-specific approved-assay paper result was available to verify rescue of ATM-specific phosphorylation targets, radiosensitivity, or both.

Sources

Reasoning

The ATM VCEP BP2 framework assigns negative points only for unaffected non-A-T adults older than 18 years who carry this variant with a pathogenic or likely pathogenic ATM variant in trans, with point values determined by confirmed trans, phase unknown, or laboratory/database setting. The case evidence contains no unaffected adult observation, no documented non-A-T phenotype, no co-occurring pathogenic or likely pathogenic ATM variant, and no phase information for NM_000051.4:c.3285-15C>T (NP_000042.3:p.?). The governing file ATM_PM3_BP2_1.5.pdf was searched for c.3285-15C>T and p.? and contains no variant-specific entry; consequently no BP2 points or strength can be assigned.

Rule

ATM VCEP BP2: assign negative points from unaffected non-A-T adults with a pathogenic/likely pathogenic ATM variant; BP2 Supporting=-1.0, Moderate=-2.0, Strong at -4.0 or less.

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 restricts BP2 to unaffected non-A-T adults older than 18 years carrying the variant with a pathogenic or likely pathogenic ATM variant, and assigns -4.0 points for confirmed trans, -2.0 for phase unknown, or -2.0/-1.0 for homozygous laboratory/database observations.
• The same VCEP table converts BP2 totals to Supporting at -1.0, Moderate at -2.0, and Strong at -4.0 or less.
• The consolidated allelic evidence contained no unaffected-adult, non-A-T, pathogenic-in-trans, homozygous, or phase observation for NM_000051.4:c.3285-15C>T.
• Direct search of ATM_PM3_BP2_1.5.pdf for c.3285-15C>T and p.? found no variant-specific entry.

Still missing

• No documented unaffected non-A-T adult older than 18 years carrying the variant.
• No documented pathogenic or likely pathogenic ATM variant in the same individual.
• No parental or other phase evidence establishing trans or phase-unknown status.
• No entry for c.3285-15C>T or p.? was found when ATM_PM3_BP2_1.5.pdf was searched.

Sources