NM_033360.3:c.34_35delGGTGGinsTGTGC

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GRCh37: None · GRCh38: None

Gene: Transcript:

Final call

VUS

Variant details

Gene

Transcript

Protein

gnomAD AF

ClinVar

None

OncoKB

None

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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 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	KRAS (NM_033360.3) germline disorders (RASopathies: Noonan syndrome, cardio-facio-cutaneous syndrome) are caused by gain-of-function activating mutations, not loss-of-function. This variant is an in-frame indel that preserves the reading frame; null variants are not the established disease mechanism for KRAS. PVS1 is not applicable for gain-of-function disease genes.	pvs1_generic_framework
PS1	N/A	PS1 requires a different nucleotide change at the same amino acid position previously established as pathogenic. This is a complex in-frame indel altering multiple amino acids at codons 12-13, not a single-nucleotide missense change amenable to PS1 comparison.
PS2	Not assessed	No de novo data available in the case files. No publications were retrieved that could provide de novo evidence for this variant.
PS3	Not assessed	No functional study data for this variant was retrieved in the case files. Well-established functional evidence exists in the broader literature for individual KRAS G12V and G13C mutations in oncogenic contexts, but no variant-specific functional data for NM_033360.3:c.34_35delGGTGGinsTGTGC was available for review.
PS4	Not assessed	No case-control or cohort data available in the case files. Population frequency data could not be retrieved due to normalization failure during prefetch.
PS5	N/A	PS5 is not part of the standard ACMG/AMP 2015 criteria (Richards et al., PMID:25741868). It is used in some VCEP frameworks as a moderated PS4 but is not applicable under the generic ACMG classification in use for this case.	generic_acmg_combination_rules
PM1	Not assessed	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. However, database evidence (hotspot lookups, gnomAD benign variation confirmation) could not be retrieved because variant normalization failed during prefetch (VariantValidator unavailable). PM1 would likely be met at moderate strength if population and domain data were available.
PM2	Not assessed	Population frequency data from gnomAD v2.1 and v4.1 could not be retrieved due to normalization failure. gnomAD-Canada returned AN=0 (no alleles queried at this position), which is not informative. PM2 cannot be assessed without valid population allele frequency data.
PM4	Not assessed	PM4 applies to in-frame deletions/insertions in a non-repeat region that change protein length. The variant is a complex indel but the protein consequence could not be determined because normalization failed (VariantValidator unavailable). Additionally, the HGVS notation is flagged: the deletion length (5 bases: GGTGG) does not match the coordinate range (c.34_35, 2 positions). LOVD suggests NM_033360.3:c.34_35delinsTGTGC (2-base deletion, 5-base insertion = net +1 amino acid). PM4 cannot be reliably assessed until the correct HGVS and protein consequence are resolved.
PM5	N/A	PM5 applies to a novel missense change at the same amino acid residue as a previously established pathogenic missense variant. This is a complex in-frame indel, not a missense variant. No same-residue missense comparators could be identified (pm5_candidates.json reports not_applicable mode).	pm5_candidates
PM6	Not assessed	No de novo data available in the case files. No publications were retrieved that could provide de novo evidence with confirmed or unconfirmed parentage for this variant.
PP1	Not assessed	No co-segregation data available in the case files. No family studies or pedigrees were retrieved for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. This is a complex in-frame indel, not a missense variant. Additionally, the gene-level constraint data (HCI prior) could not be retrieved.
PP3	Not assessed	In silico computational evidence could not be assessed. REVEL and BayesDel were skipped (not applicable to indels). SpliceAI scores are null because variant normalization failed. No other computational predictors are available in the case files.
PP4	Not assessed	No patient phenotype or clinical data available in the case files. PP4 requires that the patient's phenotype or family history is highly specific for the gene/disease.
PP5	Not assessed	ClinVar data could not be retrieved for this variant. No reputable source classification is available in the case files.
BA1	Not assessed	Population allele frequency data from gnomAD could not be retrieved due to normalization failure. BA1 (>1% allele frequency) cannot be assessed without valid population frequency data.
BS1	Not assessed	Population allele frequency data from gnomAD could not be retrieved due to normalization failure. BS1 (>0.3% allele frequency) cannot be assessed without valid population frequency data.
BS2	Not assessed	No observational data on healthy adult carriers available. BS2 requires observation of the variant in healthy individuals with full penetrance expected at an early age.
BS3	Not assessed	No functional study data was retrieved for this variant. BS3 requires well-established functional studies demonstrating no deleterious effect.
BS4	Not assessed	No segregation data available. BS4 requires lack of segregation with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a complex in-frame indel, not a missense variant. Additionally, KRAS germline disease (RASopathies) is driven by gain-of-function activating mutations, not truncating loss-of-function.
BP2	Not assessed	No phase data available. BP2 requires observation of the variant in trans with a pathogenic variant in a recessive disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP3	N/A	BP3 applies to in-frame deletions/insertions in a repetitive region without a known function. The variant is in KRAS codons 12-13 within the P-loop/G1 motif, a well-established critical functional domain, not a nonfunctional repetitive region.
BP4	Not assessed	In silico computational evidence could not be assessed. REVEL and BayesDel were skipped (not applicable to indels). SpliceAI scores are null due to normalization failure.
BP5	Not assessed	No data on alternate molecular basis for disease in a case carrying this variant. BP5 requires the variant to be found in a case with an established alternate molecular cause.
BP6	Not assessed	ClinVar data could not be retrieved. BP6 requires a reputable source to report the variant as benign.
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splicing impact and low nucleotide conservation. This variant is a complex in-frame indel, not a synonymous variant.

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