NM_033360.3:c.34_35delGGTGGinsTGTGC is a complex in-frame indel in KRAS affecting codons 12-13 within the P-loop/G1 motif, a critical functional domain and well-established mutational hotspot. Most ACMG/AMP criteria could not be assessed because variant normalization failed during the evidence retrieval phase (VariantValidator unavailable), resulting in absent population frequency data, absent ClinVar classifications, and absent functional evidence in the case files. PVS1 is not applicable: KRAS germline disorders (RASopathies: Noonan syndrome, CFC syndrome) are caused by gain-of-function activating mutations, not loss-of-function, and this is an in-frame indel that does not trigger nonsense-mediated decay.1 Re-adjudication is recommended after successful variant normalization to obtain gnomAD allele frequencies, ClinVar classifications, SpliceAI scores, and to correct the HGVS notation (which has a coordinate-range vs deletion-sequence-length mismatch flagged by VariantValidator). PM1 (hotspot domain), PM2 (absent from population), and PM4 (in-frame indel in non-repeat region) are likely to be the most informative criteria once data are available.
Final classification
VUS
c.34_35delGGTGGinsTGTGC
NM_033360.3:c.34_35delGGTGGinsTGTGC is a complex in-frame indel in KRAS affecting codons 12-13 within the P-loop/G1 motif, a critical functional domain and well-established mutational hotspot. Most ACMG/AMP criteria could not be assessed because variant normalization failed during the evidence retrieval phase (VariantValidator unavailable), resulting in absent population frequency data, absent ClinVar classifications, and absent functional evidence in the case files.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: none; combination = no applied criteria, which maps to VUS.
Classification rationale
VUS
c.34_35delGGTGGinsTGTGC
Applied criteria · 0 applied · 20 assessed
Applied · 0
No criteria were applied for this variant.
Assessed · not applied
Pathogenic
PS2
No de novo data available in the case files.
PS3
No functional study data for this variant was retrieved in the case files.
PS4
No case-control or cohort data available in the case files.
PM1
The variant alters codons 12-13 of KRAS, which reside within the phosphate-binding loop (P-loop / G1 motif, residues 10-17) — a well-established critical functional domain and mutational hotspot.
PM2
Population frequency data from gnomAD v2.1 and v4.1 could not be retrieved due to normalization failure.
PM4
PM4 applies to in-frame deletions/insertions in a non-repeat region that change protein length.
PM6
No de novo data available in the case files.
PP1
No co-segregation data available in the case files.
PP3
In silico computational evidence could not be assessed.
PP4
No patient phenotype or clinical data available in the case files.
PP5
ClinVar data could not be retrieved for this variant.
Benign
BA1
Population allele frequency data from gnomAD could not be retrieved due to normalization failure.
BS1
Population allele frequency data from gnomAD could not be retrieved due to normalization failure.
BS2
No observational data on healthy adult carriers available.
BS3
No functional study data was retrieved for this variant.
BS4
No segregation data available.
BP2
No phase data available.
BP4
In silico computational evidence could not be assessed.
BP5
No data on alternate molecular basis for disease in a case carrying this variant.
BP6
ClinVar data could not be retrieved.
N/A · 7
PVS1 · PS1 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
v4.1
This variant is absent from gnomAD v4.1.
v2.1
This variant is absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
No data
No ClinVar submissions were recorded for this variant.
In silico
No data
No in-silico prediction was recorded for this variant.
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
No sources recorded.