Variant classification summary

NM_001184.3:c.5459_5460insC

ATR · NP_001175.2:p.(Asp1821Ter) · NM_001184.3

GRCh37: chr3:142217537 A>AG · GRCh38: chr3:142498695 A>AG

Gene: ATR Transcript: NM_001184.3

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

ATR

Transcript

NM_001184.3

Protein

NP_001175.2:p.(Asp1821Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001184.3:c.5459_5460insC (p.Asp1821Ter) is a nonsense variant in ATR, where loss-of-function is an established mechanism for Seckel syndrome type 1. The premature termination codon at position 1821 of 2645 is expected to trigger nonsense-mediated decay, satisfying PVS1 at very strong evidence level under ClinGen SVI PVS1 recommendations (PMC6185798).

2

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting PM2 at moderate evidence level.

3

No benign criteria are met. BA1 and BS1 are not satisfied (allele frequency 0%). BS2, BS3, BS4, BP2, BP4, BP5, and BP6 are not met or not assessed due to insufficient data.

4

Under generic ACMG/AMP 2015 combination rules (PMID:25741868), one very strong criterion (PVS1) plus one moderate criterion (PM2) supports a Likely Pathogenic classification.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	Nonsense variant (p.Asp1821Ter) in ATR, where loss-of-function is an established disease mechanism for Seckel syndrome. The premature termination codon at position 1821 of 2645 resides well upstream of the last exon; nonsense-mediated decay is expected. Under ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at very strong evidence level.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 requires a nucleotide substitution that predicts the same amino acid change as an established pathogenic missense variant. This variant is a 1-bp insertion causing a frameshift and premature termination, not a substitution.
PS2	Not assessed	No confirmed de novo occurrence with established maternity and paternity has been reported for NM_001184.3:c.5459_5460insC. The variant is absent from ClinVar and no family studies identifying a de novo event were identified.
PS3	Not assessed	No variant-specific functional studies demonstrating a damaging effect on ATR protein function were identified. Available publications (PMID:10691732, PMID:15282542) discuss ATR loss-of-function at the gene level but do not mention NM_001184.3:c.5459_5460insC.
PS4	Not assessed	No case-control study comparing the prevalence of this variant in affected versus unaffected individuals is available. The variant is absent from gnomAD and ClinVar, precluding statistical enrichment analysis.
PS5	N/A	PS5 applies when a variant is assumed de novo with unconfirmed parentage. No de novo observation, assumed or confirmed, has been reported for this variant.
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot or a well-characterized critical functional domain without benign variation, per cancerhotspots.org analysis.
PM2	Met	NM_001184.3:c.5459_5460insC is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare pathogenic variant. Under generic ACMG/AMP 2015, absence from population databases supports PM2 at moderate strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is a frameshift insertion leading to a premature termination codon, assessed under PVS1.
PM5	N/A	PM5 requires a different pathogenic missense change at the same codon. This variant creates a premature termination codon at Asp1821, and no qualifying same-residue comparator variants were identified in the PM5 candidate search.
PM6	Not assessed	No de novo observation (assumed or confirmed) has been reported for this variant. For the autosomal recessive Seckel syndrome, a single de novo heterozygous variant would not be sufficient; PM6 is rarely applicable in this context.
PP1	Not assessed	No co-segregation data are available for this variant. No family with multiple affected members carrying this variant has been reported.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. This variant is a frameshift insertion producing a nonsense change, not a missense variant.
PP3	Not met	No in silico prediction tools (REVEL, BayesDel) provide scores for insertion variants. SpliceAI predicts no splice impact (max delta score 0.00). Multiple lines of computational evidence supporting a deleterious effect are not satisfied.	spliceai
PP4	Not assessed	No detailed patient phenotype information is available for individuals carrying this variant. Without specific phenotype data, the specificity of the patient's presentation cannot be evaluated.
PP5	Not assessed	No reputable source (e.g., clinical diagnostic laboratory) has independently classified NM_001184.3:c.5459_5460insC. The variant is absent from ClinVar.
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from population databases. Allele frequency is 0%, well below the BS1 threshold of >0.3% for a rare disease.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The variant has not been observed in healthy adult individuals to satisfy BS2 criteria. Its absence from all population databases precludes application of this criterion.
BS3	Not assessed	No variant-specific functional studies demonstrating no damaging effect on ATR protein function are available. Gene-level functional studies (PMID:10691732, PMID:15282542) establish ATR loss-of-function as pathogenic, which supports pathogenicity rather than benignity.
BS4	Not met	No family studies demonstrating lack of segregation between this variant and disease have been reported. In the absence of such data, BS4 cannot be applied.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is itself a truncating (nonsense) variant.
BP2	Not met	No observation of this variant in trans with a pathogenic ATR variant in a healthy individual, or in cis with a pathogenic variant, has been reported. The variant's extreme rarity precludes such observations.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. This variant is a frameshift insertion leading to a premature termination codon, not an in-frame indel.
BP4	Not met	Multiple lines of computational evidence suggesting no impact are not satisfied. SpliceAI predicts no splice alteration (delta 0.00), but REVEL and BayesDel are unavailable for insertion variants, leaving only one line of computational evidence instead of the multiple required for BP4.	spliceai
BP5	Not met	No observation of this variant in a case where an alternative molecular basis for the disease has been identified.
BP6	Not met	No reputable source has classified this variant as benign or likely benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift insertion causing a premature termination codon, not a synonymous change.
PM3	N/A	Skipped by directive.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.