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c.34_35delGGTGGinsTGTGCUncertain significance

Print report

Variant interpretation report

c.34_35delGGTGGinsTGTGC

NM_033360.3:c.34_35delGGTGGinsTGTGC View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About the gene

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 0

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

No listed criterion applied gnomAD-Canada ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied

No screenshot for this evidence

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied

No screenshot for this evidence

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Context only

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 0 met · 0 not met · 20 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

Not assessed · 20 · no assessment recorded

PS2 No de novo data available in the case files. No publications were retrieved that could provide de novo evidence for this variant. Details ▾Hide ▴

Still missing

No de novo testing data available
No publications with variant-specific proband or parent data

PS3 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. Details ▾Hide ▴

Still missing

No variant-specific functional assays retrieved
Individual KRAS G12V and G13C mutations have well-established functional evidence but the composite indel has not been assessed in the case files

PS4 No case-control or cohort data available in the case files. Population frequency data could not be retrieved due to normalization failure during prefetch. Details ▾Hide ▴

Still missing

No case-control data
No affected-individual counts
No cohort studies retrieved

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. 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. Details ▾Hide ▴

Evidence considered

KRAS codons 12-13 = P-loop/G1 motif critical functional domain (well-established biological knowledge)
No benign variation data retrievable from case files

Still missing

No gnomAD benign variation data to confirm absence of benign variants in the P-loop domain
No hotspot database confirmation retrievable
Variant normalization failed — rerun with available VariantValidator to populate domain evidence

PM2 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: null
gnomAD v4.1: null
gnomAD-Canada: AN=0
not informative

Still missing

gnomAD v2.1 and v4.1 allele frequencies unavailable
Variant normalization required before population frequency can be queried

PM4 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. Details ▾Hide ▴

Evidence considered

Variant is an in-frame indel in a known non-repeat region (KRAS P-loop)
HGVS notation is flagged by VariantValidator and LOVD
Protein consequence not resolved

Still missing

HGVS notation requires correction (position range vs deletion sequence length mismatch)
Protein consequence not determined
Normalization required to confirm in-frame status and amino acid change

PM6 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. Details ▾Hide ▴

Still missing

No de novo testing data available
No publications with variant-specific parentage data

PP1 No co-segregation data available in the case files. No family studies or pedigrees were retrieved for this variant. Details ▾Hide ▴

Still missing

No segregation data available
No family studies retrieved

PP3 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. Details ▾Hide ▴

Evidence considered

REVEL: skipped (not SNV)
BayesDel: skipped (not SNV)
SpliceAI: null (normalization failed)

Still missing

No SpliceAI scores available
No in silico predictors applicable to indels in the case files

PP4 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. Details ▾Hide ▴

Still missing

No patient phenotype data
No clinical history information in the case files

PP5 ClinVar data could not be retrieved for this variant. No reputable source classification is available in the case files. Details ▾Hide ▴

Evidence considered

ClinVar: no data retrieved (normalization failed)

Still missing

ClinVar data not available
No submitter classifications retrieved

BA1 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: null
gnomAD v4.1: null

Still missing

Population allele frequency data unavailable

BS1 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: null
gnomAD v4.1: null

Still missing

Population allele frequency data unavailable

BS2 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. Details ▾Hide ▴

Still missing

No healthy carrier data available
No penetrance data for this variant

BS3 No functional study data was retrieved for this variant. BS3 requires well-established functional studies demonstrating no deleterious effect. Details ▾Hide ▴

Still missing

No functional studies in case files

BS4 No segregation data available. BS4 requires lack of segregation with disease in affected family members. Details ▾Hide ▴

Still missing

No family segregation data available

BP2 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. Details ▾Hide ▴

Still missing

No phase data (in trans/in cis) available

BP4 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. Details ▾Hide ▴

Evidence considered

REVEL: skipped (not SNV)
BayesDel: skipped (not SNV)
SpliceAI: null

Still missing

No in silico scores available for this variant type

BP5 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. Details ▾Hide ▴

Still missing

No alternate molecular diagnosis data available

BP6 ClinVar data could not be retrieved. BP6 requires a reputable source to report the variant as benign. Details ▾Hide ▴

Evidence considered

ClinVar: no data retrieved

Still missing

ClinVar classification data unavailable

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AKRAS (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. Details ▾Hide ▴

Evidence considered

KRAS germline disease mechanism is gain-of-function
not loss-of-function
Variant is an in-frame indel
not a null variant

Sources

pvs1_generic_framework ↗

PS1 N/APS1 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. Details ▾Hide ▴

Evidence considered

Variant is a complex indel
not a single-nucleotide substitution at a single amino acid position

PM5 N/APM5 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). Details ▾Hide ▴

Evidence considered

Variant is an indel
not a missense change
PM5 candidate harvesting returned no candidates (not_applicable mode)

Sources

pm5_candidates

PP2 N/APP2 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. Details ▾Hide ▴

Evidence considered

Variant is an indel
not a missense change
PP2 is defined for missense variants

BP1 N/ABP1 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. Details ▾Hide ▴

Evidence considered

Variant is an indel
not a missense
KRAS disease mechanism is gain-of-function
not truncating

BP3 N/ABP3 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. Details ▾Hide ▴

Evidence considered

Variant is in the P-loop functional domain (codons 10-17)
not a repetitive region without known function

BP7 N/ABP7 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. Details ▾Hide ▴

Evidence considered

Variant is a complex indel
not a synonymous substitution

PS5 N/APS5 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. Details ▾Hide ▴

Evidence considered

PS5 is not defined in the standard 2015 ACMG/AMP framework

Sources

generic_acmg_combination_rules

Identifiers

Coding (HGVS c.): NM_033360.3:c.34_35delGGTGGinsTGTGC

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

No population statements were recorded.

Open the gnomAD-Canada detail page →

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

PP3 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. Details ▾Hide ▴

Evidence considered

REVEL: skipped (not SNV)
BayesDel: skipped (not SNV)
SpliceAI: null (normalization failed)

Still missing

No SpliceAI scores available
No in silico predictors applicable to indels in the case files

BP4 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. Details ▾Hide ▴

Evidence considered

REVEL: skipped (not SNV)
BayesDel: skipped (not SNV)
SpliceAI: null

Still missing

No in silico scores available for this variant type

BP7 N/ABP7 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. Details ▾Hide ▴

Evidence considered

Variant is a complex indel
not a synonymous substitution

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.