Variant classification summary

NM_000051.4:c.7927+13T>A

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108203640 T>A · GRCh38: chr11:108332913 T>A

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.?

gnomAD AF

7.45528691671699e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

c.7927+13T>A is present at extremely low frequency in gnomAD v4.1 (AF = 0.00075%, 12/1,609,596 alleles, 0 homozygotes; grpmax FAF = 5.01e-06), meeting the ATM HBOP VCEP threshold for PM2_Supporting (≤0.001%).

2

SpliceAI predicts no significant splicing impact (max delta score = 0.03), meeting BP4_Supporting per the ATM HBOP VCEP threshold of ≤0.1.

3

The variant is at the donor +13 position, beyond the +7 deep intronic boundary, meeting BP7_Supporting per the ATM HBOP VCEP as a deep intronic variant unlikely to affect splicing.

4

Two lines of benign supporting evidence (BP4, BP7) are present. Applying ACMG/AMP 2015 combination rules (Richards et al. 2015, PMID:25741868), two benign supporting criteria meet the threshold for Likely Benign (Rule 19).

Final determination: Rule19 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

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	Not met	NM_000051.4:c.7927+13T>A is an intronic substitution at the donor +13 position, outside the canonical ±1,2 splice consensus. SpliceAI predicts no significant splice impact (max delta score = 0.03). The ATM HBOP VCEP PVS1 decision tree requires either a predicted or observed splice defect; neither is present for this variant.	spliceai vcep_atm_pvs1_1_5
PS1	Not met	No comparator pathogenic or likely pathogenic splicing variant with a similar predicted splicing event has been identified for c.7927+13T>A. The ATM PS1 splicing table requires a reference P/LP variant with matching predicted event, which is not available.	vcep_atm_ps1_1_5
PS2	N/A	ATM HBOP VCEP does not permit use of PS2 for autosomal dominant or autosomal recessive disease; informative de novo occurrences have not been observed for ATM.	cspec
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a damaging effect on ATM protein function or splicing have been identified for c.7927+13T>A.
PS4	Not met	No case-control studies demonstrating significant enrichment of c.7927+13T>A in affected individuals versus controls have been identified. The ATM VCEP requires a case-control study with p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5.
PS5	N/A	PS5 is not defined in the ATM HBOP VCEP criteria set and is not used in this framework.	cspec
PM1	N/A	ATM HBOP VCEP does not permit use of PM1; benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined.	cspec
PM2	Met	c.7927+13T>A is present at extremely low frequency in gnomAD v4.1 (AF = 0.00075%, 12/1,609,596 alleles, 0 homozygotes; grpmax FAF = 5.01e-06). This frequency is ≤0.001%, meeting the ATM HBOP VCEP threshold for PM2_Supporting.	gnomad_v4 cspec
PM5	N/A	ATM HBOP VCEP PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with PVS1_VS(RNA) applied based on high-quality observed splicing impact. c.7927+13T>A is an intronic substitution at +13 and does not meet either condition.	cspec
PM6	N/A	ATM HBOP VCEP does not permit use of PM6; informative de novo occurrences have not been observed for ATM.	cspec
PP1	Not met	No segregation data are available for c.7927+13T>A. The ATM VCEP applies PP1 only for autosomal recessive conditions with segregation in affected relatives; AD co-segregation is not used due to low penetrance.
PP2	N/A	ATM HBOP VCEP does not permit use of PP2; ATM does not have a defined low rate of benign missense variation.	cspec
PP3	Not met	SpliceAI predicts no significant splicing impact (max delta score = 0.03). The ATM HBOP VCEP PP3 threshold for splicing variants is SpliceAI ≥0.2, which is not met. No other computational evidence supports a deleterious effect.	spliceai cspec
PP4	N/A	ATM HBOP VCEP does not permit use of PP4 due to genetic heterogeneity of breast cancer and because A-T phenotype evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for the ATM HBOP VCEP.	cspec
BA1	Not met	gnomAD v4.1 grpmax filtering allele frequency is 5.01e-06 (0.000501%), which is not >0.5%. The ATM HBOP VCEP BA1 threshold is not met.	gnomad_v4 cspec
BS1	Not met	gnomAD v4.1 grpmax filtering allele frequency is 5.01e-06 (0.000501%), which is not >0.05%. The ATM HBOP VCEP BS1 threshold is not met.	gnomad_v4 cspec
BS2	N/A	ATM HBOP VCEP does not permit use of BS2; ATM has incomplete penetrance.	cspec
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on ATM protein function or splicing have been identified for c.7927+13T>A.
BS4	N/A	ATM HBOP VCEP does not permit use of BS4; co-segregation analysis in low-penetrance genes can lead to false positive results for AD conditions, and informative instances of lack of co-segregation in A-T families are too rare.	cspec
BP1	N/A	ATM HBOP VCEP does not permit use of BP1; missense pathogenic variants are known for ATM.	cspec
BP2	Not met	No data are available regarding observation of c.7927+13T>A in trans with a pathogenic ATM variant in unaffected individuals. The ATM PM3/BP2 table requires proband-level data to assign points; none are available.
BP4	Met	SpliceAI predicts no splicing impact for c.7927+13T>A (max delta score = 0.03). This is ≤0.1, meeting the ATM HBOP VCEP BP4 threshold for no predicted splicing impact.	spliceai cspec
BP5	N/A	ATM HBOP VCEP does not permit use of BP5; cases with multiple pathogenic variants have been observed in ATM with no noticeable difference in phenotype.	cspec
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee for the ATM HBOP VCEP.	cspec
BP7	Met	c.7927+13T>A is an intronic variant at the donor +13 position, which is further than (but not including) +7. This meets the ATM HBOP VCEP BP7 definition for deep intronic variants unlikely to affect splicing.	cspec

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