LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_000051.3:c.4818dupT
ATM
· NP_000042.3:p.(Pro1607SerfsTer6)
· NM_000051.3
GRCh37: chr11:108165693 C>CT
·
GRCh38: chr11:108294966 C>CT
Gene:
ATM
Transcript:
NM_000051.3
Final call
Pathogenic
PVS1 very strong
PM2 supporting
PM5 supporting
Variant details
Gene
ATM
Transcript
NM_000051.3
Protein
NP_000042.3:p.(Pro1607SerfsTer6)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_000051.3:c.4818dupT (p.Pro1607SerfsTer6) is a frameshift duplication in exon 32 of ATM predicted to cause nonsense-mediated decay and complete loss of ATM protein function (PVS1_VeryStrong).
2
The variant is absent from gnomAD v4.1 population database (0/1,614,094 alleles), meeting the ATM VCEP PM2_Supporting threshold of ≤0.001% allele frequency.
3
The premature termination codon at p.Pro1607SerfsTer6 lies upstream of p.Arg3047, satisfying the ATM VCEP PM5_Supporting rule for frameshifting variants with PTCs upstream of this C-terminal boundary.
4
No variant-specific functional studies, case-control data, co-segregation data, or co-occurrence data were identified for this variant in the literature screened (PMID:27413114, PMID:30348496, PMID:30553448).
5
The variant is not present in ClinVar and has not been reported in COSMIC or in statistically significant mutational hotspots.
Final determination:
Rule4 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 Pathogenic.
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 | Frameshift variant NM_000051.3:c.4818dup (p.Pro1607SerfsTer6) creates a premature termination codon at residue 1612 in ATM, a gene where loss of function is an established mechanism for ataxia-telangiectasia and hereditary breast/ovarian/pancreatic cancer. The PTC is NMD-competent and lies well upstream of the C-terminal boundary (p.Arg3047) specified by the ATM VCEP v1.5.0 PVS1 decision tree. PVS1_VeryStrong applied per ClinGen HBOP VCEP specifications. |
cspec
pvs1_generic_framework
|
| PS1 | N/A | PS1 under ATM VCEP v1.5.0 applies to missense changes or splicing variants with a same-nucleotide comparator. This is a frameshift duplication variant. |
cspec
|
| PS2 | N/A | PS2 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| PS3 | Not assessed | No variant-specific functional studies were identified for NM_000051.3:c.4818dupT. Three papers retrieved through literature screening (PMID:27413114, PMID:30348496, PMID:30553448) discuss ATM gene-level biology and functional pathways but do not mention or study this specific variant. |
|
| PS4 | Not assessed | No case-control study data are available for NM_000051.3:c.4818dupT. ATM VCEP v1.5.0 requires case-control studies with p-value ≤0.05 AND (OR ≥2 OR lower 95% CI ≥1.5) for PS4_Strong. |
|
| PS5 | N/A | PS5 is not defined in the ATM VCEP v1.5.0 criteria specifications. This criterion is excluded by the VCEP framework. |
cspec
|
| PM1 | N/A | PM1 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| PM2 | Met | NM_000051.3:c.4818dupT is absent from gnomAD v4.1 (0 alleles, AF=0), satisfying the ATM VCEP PM2_Supporting threshold of ≤0.001% population frequency. |
gnomad_v4
|
| PM4 | N/A | PM4 under ATM VCEP v1.5.0 is restricted to stop-loss variants. NM_000051.3:c.4818dupT is a frameshift duplication, not a stop-loss variant. |
cspec
|
| PM5 | Met | This frameshift variant creates a premature termination codon at p.Pro1607SerfsTer6 (PTC at codon 1612), which lies upstream of p.Arg3047, satisfying the ATM VCEP v1.5.0 PM5_Supporting rule for frameshifting/truncating variants with PTCs upstream of p.Arg3047. |
cspec
|
| PM6 | N/A | PM6 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| PP1 | Not assessed | No co-segregation data are available for NM_000051.3:c.4818dupT. ATM VCEP v1.5.0 PP1 applies to autosomal recessive A-T (segregation in affected relatives); no family studies identified. |
|
| PP2 | N/A | PP2 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| PP3 | N/A | PP3 under ATM VCEP v1.5.0 applies to missense variants (REVEL >0.7333) or splicing/silent/intronic variants (SpliceAI ≥0.2). NM_000051.3:c.4818dupT is a frameshift duplication and does not fall under these categories. |
cspec
|
| PP4 | N/A | PP4 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| PP5 | N/A | PP5 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| BA1 | Not met | NM_000051.3:c.4818dupT is absent from gnomAD v4.1 (0 alleles). Does not meet the ATM VCEP BA1 threshold of grpmax filtering allele frequency >0.5%. |
gnomad_v4
|
| BS1 | Not met | NM_000051.3:c.4818dupT is absent from gnomAD v4.1 (0 alleles). Does not meet the ATM VCEP BS1 threshold of grpmax filtering allele frequency >0.05%. |
gnomad_v4
|
| BS2 | N/A | BS2 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| BS3 | Not assessed | No variant-specific functional rescue data are available for NM_000051.3:c.4818dupT. ATM VCEP v1.5.0 BS3 requires evidence that a variant rescues ATM-specific features (e.g., phosphorylation of ATM-specific targets) and/or radiosensitivity; no such studies identified. |
|
| BS4 | N/A | BS4 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| BP1 | N/A | BP1 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| BP2 | Not assessed | No co-occurrence data in trans with a known pathogenic ATM variant are available for NM_000051.3:c.4818dupT. ATM VCEP BP2 requires proband-level data with points assigned per the PM3/BP2 table; no such data identified. |
|
| BP3 | N/A | BP3 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| BP4 | N/A | BP4 under ATM VCEP v1.5.0 applies to missense variants (REVEL ≤0.249) or splicing variants (SpliceAI ≤0.1). NM_000051.3:c.4818dupT is a frameshift duplication and does not fall under these categories. |
cspec
|
| BP5 | N/A | BP5 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| BP6 | N/A | BP6 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. |
cspec
|
| BP7 | N/A | BP7 under ATM VCEP v1.5.0 applies to synonymous and deep intronic variants. NM_000051.3:c.4818dupT is a frameshift duplication and does not fall under these categories. |
cspec
|
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.