Variant classification summary

NM_004958.4:c.3610A>G

MTOR · NP_004949.1:p.(Ile1204Val) · NM_004958.4

GRCh37: chr1:11270915 T>C · GRCh38: chr1:11210858 T>C

Gene: MTOR Transcript: NM_004958.4

Final call

VUS

PM2 supporting

Variant details

Gene

MTOR

Transcript

NM_004958.4

Protein

NP_004949.1:p.(Ile1204Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_004958.4:c.3610A>G (p.Ile1204Val) is a missense variant in the MTOR gene, which is associated with cerebral malformation via a gain-of-function mechanism (Brain Malformations CSPEC v1.1).

2

This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength under the Brain Malformations CSPEC.

3

No pathogenic or benign classifications exist in ClinVar; the variant has not been reported in any clinical or research database.

4

No functional studies, case reports, de novo observations, or segregation data are available for this variant. OncoKB classifies the variant as Unknown Oncogenic Effect.

5

The CSPEC framework marks 13 criteria as not applicable for MTOR variant assessment: PVS1 (GOF mechanism), PM6 (addressed under PS2), PP1 (mosaic/de novo), PP3 (LOF-focused algorithms), PP4 (accounted under PS4), PP5 (SVI recommendation), BS4 (de novo/mosaic), BP1 (LOF not mechanism), BP4 and BP7 (not applicable to missense), BP6 (SVI recommendation).

6

With only one supporting-level pathogenic criterion (PM2_supporting) met and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	N/A	The Brain Malformations CSPEC (v1.1) explicitly marks PVS1 as not applicable for MTOR. Loss of function and haploinsufficiency have not been established as disease mechanisms; the disease mechanism for MTOR is gain of function (GOF). This variant is a missense substitution (p.Ile1204Val) and would not qualify under the generic PVS1 framework regardless.	cspec
PS1	Not met	No different nucleotide change at codon 1204 that produces the same p.Ile1204Val amino acid change has been established as pathogenic. The variant is absent from ClinVar entirely with no submissions at this residue.	clinvar
PS2	Not met	No de novo observation has been reported for NM_004958.4:c.3610A>G. The CSPEC requires evidence of somatic mosaicism (detectable allele fraction in affected tissue absent from parental samples) for PS2_strong, or confirmed de novo for PS2_moderate. Neither criterion is met.
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified for p.Ile1204Val. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional evidence. No published literature with functional characterization of this variant was identified.	oncokb
PS4	Not met	No affected individuals harboring NM_004958.4:c.3610A>G have been reported in the literature or clinical databases (ClinVar, COSMIC). The CSPEC PS4 point system cannot be applied in the absence of any case-level data.	clinvar
PS5	N/A	PS5 is not a recognized ACMG/AMP criterion. The standard pathogenic criteria are PVS1 and PS1 through PS4. PS5 does not exist in either the generic ACMG/AMP 2015 framework (PMID:25741868) or the Brain Malformations CSPEC v1.1.
PM1	Not met	The CSPEC restricts PM1 to supporting-strength for residues affecting critical functional domains as specified in Table 4. Table 4 is not available in the VCEP materials for review. Additionally, p.Ile1204 is not located in a statistically significant hotspot per cancerhotspots.org, and the residue lies in a region of MTOR outside the kinase domain (residues ~2182-2516) that harbors most known pathogenic missense variants.
PM2	Met	NM_004958.4:c.3610A>G is absent from all population databases (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0). Under the Brain Malformations CSPEC v1.1, PM2 is applied at supporting strength for variants absent/rare from controls in an ethnically-matched cohort population sample.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at amino acid residue 1204 of MTOR has been identified in ClinVar or the literature. The standard PM5 criterion requires a different amino acid change at the same residue to be established as pathogenic, which is not available for this variant.	clinvar pm5_candidates
PM6	N/A	The Brain Malformations CSPEC v1.1 explicitly marks PM6 as not applicable. Assumed de novo without confirmation of paternity and maternity is addressed under the modified PS2 criterion.	cspec
PP1	N/A	The Brain Malformations CSPEC v1.1 explicitly marks PP1 as not applicable. Disease-causing variants are germline mosaic, de novo, or mosaic, making co-segregation analysis infeasible.	cspec
PP2	Not met	The CSPEC awards PP2 at supporting strength when the gnomAD missense constraint z-score exceeds 3.09 for MTOR. The missense z-score was not available in the evidence packet. Without this metric, the criterion cannot be met.
PP3	N/A	The Brain Malformations CSPEC v1.1 explicitly marks PP3 as not applicable. Traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms, whereas MTOR variants act through gain of function. The REVEL score (0.186) and BayesDel score (-0.200856) are not considered applicable under this CSPEC.	cspec
PP4	N/A	The Brain Malformations CSPEC v1.1 explicitly marks PP4 as not applicable. The phenotype specificity criterion is accounted for under the CSPEC's modified PS4 scoring system.	cspec
PP5	N/A	The Brain Malformations CSPEC v1.1 explicitly marks PP5 as not applicable per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Additionally, the variant is absent from ClinVar, so no reputable source classification exists to consider.	cspec clinvar
BA1	Not met	Under the Brain Malformations CSPEC v1.1, BA1 requires an allele frequency greater than 0.0926%. NM_004958.4:c.3610A>G is absent from all gnomAD populations (v2.1, v4.1, Canada) with an observed allele frequency of 0.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Under the Brain Malformations CSPEC v1.1, BS1 requires an allele frequency greater than 0.0185%. NM_004958.4:c.3610A>G is absent from all gnomAD populations (v2.1, v4.1, Canada) with an observed allele frequency of 0.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The CSPEC awards BS2 if ≥3 homozygotes are present in gnomAD or ≥3 heterozygous individuals are observed in well-phenotyped family members. NM_004958.4:c.3610A>G is absent from all gnomAD populations; no homozygous individuals exist. No well-phenotyped heterozygous family member data is available.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on MTOR protein function have been identified for p.Ile1204Val. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional data available.	oncokb
BS4	N/A	The Brain Malformations CSPEC v1.1 explicitly marks BS4 as not applicable. Lack of segregation analysis is not applicable since these are de novo, germline mosaic, or post-zygotic mutations.	cspec
BP1	N/A	The Brain Malformations CSPEC v1.1 explicitly marks BP1 as not applicable. Missense variants in MTOR are not subject to BP1 since loss of function is not the disease mechanism.	cspec
BP2	Not met	No evidence that NM_004958.4:c.3610A>G has been observed in cis or trans with a known pathogenic variant in MTOR.
BP4	N/A	The Brain Malformations CSPEC v1.1 restricts BP4 to synonymous, intronic (except canonical splice sites), and non-coding UTR variants. NM_004958.4:c.3610A>G is a missense variant (p.Ile1204Val) and is not eligible for BP4 under this specification.	cspec
BP5	Not met	No evidence exists that NM_004958.4:c.3610A>G has been observed in a case with an alternate molecular basis for disease. No clinical case data is available for this variant.
BP6	N/A	The Brain Malformations CSPEC v1.1 explicitly marks BP6 as not applicable per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BP7	N/A	The Brain Malformations CSPEC v1.1 restricts BP7 to synonymous, intronic (except canonical splice sites), and non-coding UTR variants with PhyloP score <0.1. NM_004958.4:c.3610A>G is a missense variant (p.Ile1204Val) and is not eligible for BP7 under this specification.	cspec

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