KRASc.40G>APathogenic

Print report

Variant interpretation report

KRAS c.40G>A, p.(Val14Ile)

NM_033360.4:c.40G>A NP_203524.1:p.(Val14Ile) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

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

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About KRAS

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 3 moderate (pathogenic) · 3 supporting (pathogenic)
Expert rules: ClinGen KRAS VCEP v1.0
Other laboratories (ClinVar): 19 Pathogenic · 1 pathogenic
Pipeline record: 27 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PS3 (moderate): Three unique VCEP-approved functional assay types (RAS Activation Assay, MEK Activation Assay, ERK Activation Assay) demonstrate a damaging effect for KRAS V14I. PMID 20949621 directly tested V14I, showing approximately 30-fold increase in nucleotide exchange, accumulation in the GTP-bound state, and increased phosphorylation of MEK, ERK, and AKT. The VCEP supplemental spreadsheet lists V14I as a validated pathogenic control across all three approved assay types. Per VCEP supplemental guidance, two or more unique assay types upgrades PS3 to moderate strength.
PS4 (strong): KRAS V14I has been identified in at least 5 independent probands with RASopathy phenotypes across multiple publications and clinical laboratories. PMID 16474405 first reported V14I in Noonan syndrome. Additional probands are documented in PMID 17056636, PMID 17704260, PMID 18958496, and PMID 19020799. The variant has been classified as Pathogenic by 19 clinical laboratories and by the ClinGen RASopathy VCEP (ClinVar ID 12589), further supporting multiple independent occurrences.
PM1 (moderate): Val14 is located within the P-loop (phosphate-binding loop), an approved functional domain per the VCEP supplemental PM1 materials (HRAS residues 10-17; homologous in KRAS per Group 1: HRAS, KRAS, NRAS). The P-loop is critical for GTP/GDP binding and is a well-established mutational hotspot in RAS proteins. The variant is absent from population databases at meaningful frequency with no benign variation at this residue.
PM6 (moderate): PMID 16474405 reports KRAS V14I as a de novo germline mutation in a patient with Noonan syndrome and no family history. Paternity and maternity confirmation are not documented in the available abstract. Per VCEP PM6 moderate rule, confirmed de novo without confirmation of paternity and maternity qualifies at moderate strength.
PP2 (supporting): The VCEP explicitly states that PP2 is applicable to all RASopathy genes described and curated in the framework. KRAS is a RASopathy gene with a low rate of benign missense variation, and missense variants are a common mechanism of disease in RASopathies.
PP3 (supporting): Multiple lines of computational evidence support a deleterious effect. REVEL score is 0.803 (pathogenic range). BayesDel score is 0.29 (borderline but consistent with deleterious). SpliceAI predicts no significant splice impact (max delta 0.01). The variant substitutes a highly conserved valine with isoleucine in the P-loop, a critical functional domain.
PP5 (supporting): Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.

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 ClinGen KRAS VCEP v1.0. 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: 7 Benign evidence criteria: 0

Pathogenic criteria applied · 7

PS3Moderate

PS3 · moderate

Three unique VCEP-approved functional assay types (RAS Activation Assay, MEK Activation Assay, ERK Activation Assay) demonstrate a damaging effect for KRAS V14I. PMID 20949621 directly tested V14I, showing approximately 30-fold increase in nucleotide exchange, accumulation in the GTP-bound state, and increased phosphorylation of MEK, ERK, and AKT. The VCEP supplemental spreadsheet lists V14I as a validated pathogenic control across all three approved assay types. Per VCEP supplemental guidance, two or more unique assay types upgrades PS3 to moderate strength.

PS4Strong

PS4 · strong

KRAS V14I has been identified in at least 5 independent probands with RASopathy phenotypes across multiple publications and clinical laboratories. PMID 16474405 first reported V14I in Noonan syndrome. Additional probands are documented in PMID 17056636, PMID 17704260, PMID 18958496, and PMID 19020799. The variant has been classified as Pathogenic by 19 clinical laboratories and by the ClinGen RASopathy VCEP (ClinVar ID 12589), further supporting multiple independent occurrences.

PM1Moderate

PM1 · moderate

Val14 is located within the P-loop (phosphate-binding loop), an approved functional domain per the VCEP supplemental PM1 materials (HRAS residues 10-17; homologous in KRAS per Group 1: HRAS, KRAS, NRAS). The P-loop is critical for GTP/GDP binding and is a well-established mutational hotspot in RAS proteins. The variant is absent from population databases at meaningful frequency with no benign variation at this residue.

PM6Moderate

PM6 · moderate

PMID 16474405 reports KRAS V14I as a de novo germline mutation in a patient with Noonan syndrome and no family history. Paternity and maternity confirmation are not documented in the available abstract. Per VCEP PM6 moderate rule, confirmed de novo without confirmation of paternity and maternity qualifies at moderate strength.

PP2Supporting

PP2 · supporting

The VCEP explicitly states that PP2 is applicable to all RASopathy genes described and curated in the framework. KRAS is a RASopathy gene with a low rate of benign missense variation, and missense variants are a common mechanism of disease in RASopathies.

PP3Supporting

PP3 · supporting

Multiple lines of computational evidence support a deleterious effect. REVEL score is 0.803 (pathogenic range). BayesDel score is 0.29 (borderline but consistent with deleterious). SpliceAI predicts no significant splice impact (max delta 0.01). The variant substitutes a highly conserved valine with isoleucine in the P-loop, a critical functional domain.

PP5Supporting

PP5 · supporting

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PS4 strong, PM1 moderate, PM6 moderate, PP2 supporting, PP3 supporting, PP5 supporting; combination = 1 strong + 3 moderate + 3 supporting, which maps to Pathogenic.

02The sources

Evidence at a glance

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

gnomAD v4.1

gnomAD v2.1

Population frequency

2 / 1,612,846 alleles

gnomAD v4.1: 2 / 1,612,846 alleles. Recorded AF 1.24004e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/249502 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16070 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

20 reported laboratory submissions

19 Pathogenic · 1 pathogenic. ClinVar API review status: reviewed by expert panel.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

46 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55501342, n = 46 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen KRAS VCEP v1.0, with the data and sources behind each one.

27 criteria with recorded statuses: 7 met · 12 not met · 1 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 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_033360.4:c.40G>A (p.Val14Ile) is located in the P-loop, a critical functional domain of KRAS designated as a PM1 hotspot by the ClinGen RASopathy VCEP.

Variant-specific functional studies (PMID 20949621) demonstrate that KRAS V14I causes approximately 30-fold increase in nucleotide exchange, accumulation in the GTP-bound state, and increased downstream signaling through MEK, ERK, and AKT. Three VCEP-approved functional assay types (RAS Activation, MEK Activation, ERK Activation) confirm a damaging gain-of-function effect, satisfying PS3 at moderate strength.

KRAS V14I was first reported as a de novo germline mutation in a patient with Noonan syndrome (PMID 16474405) and has subsequently been identified in at least 5 independent probands across multiple publications, satisfying PS4 at strong strength.

The de novo occurrence without confirmed paternity and maternity satisfies PM6 at moderate strength per VCEP criteria.

PP2 applies at supporting strength per VCEP specification that PP2 is applicable to all RASopathy genes. PP3 applies at supporting strength based on REVEL score of 0.803 and multiple lines of computational evidence supporting a deleterious effect.

This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (2/1,612,846; AF=0.00012%), well below the VCEP BS1 (0.025%) and BA1 (0.05%) thresholds.

The ClinGen RASopathy Expert Panel classifies this variant as Pathogenic (ClinVar ID 12589), consistent with the evidence assessment herein.

Met · 7

PS3 ModerateThree unique VCEP-approved functional assay types (RAS Activation Assay, MEK Activation Assay, ERK Activation Assay) demonstrate a damaging effect for KRAS V14I. PMID 20949621 directly tested V14I, showing approximately 30-fold increase in nucleotide exchange, accumulation in the GTP-bound state, and increased phosphorylation of MEK, ERK, and AKT. The VCEP supplemental spreadsheet lists V14I as a validated pathogenic control across all three approved assay types. Per VCEP supplemental guidance, two or more unique assay types upgrades PS3 to moderate strength. Details ▾Hide ▴

Evidence considered

RAS Activation Assay (PMID 20949621): V14I listed as pathogenic validation control
increased GTP-bound RAS
MEK Activation Assay (PMID 20949621): V14I listed as pathogenic validation control
increased pMEK
ERK Activation Assay (PMID 20949621): V14I listed as pathogenic validation control
increased pERK
V14I showed ~30-fold increase in intrinsic and GEF-catalyzed nucleotide exchange
V14I accumulated in GTP-bound active state in COS-7 cells
V14I showed increased pMEK
pERK
and pAKT levels

Sources

PMID:20949621 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies

PS4 StrongKRAS V14I has been identified in at least 5 independent probands with RASopathy phenotypes across multiple publications and clinical laboratories. PMID 16474405 first reported V14I in Noonan syndrome. Additional probands are documented in PMID 17056636, PMID 17704260, PMID 18958496, and PMID 19020799. The variant has been classified as Pathogenic by 19 clinical laboratories and by the ClinGen RASopathy VCEP (ClinVar ID 12589), further supporting multiple independent occurrences. Details ▾Hide ▴

Evidence considered

PMID 16474405: V14I first discovered in Noonan syndrome probands
PMID 17056636: expanded genotypic spectrum of KRAS germline mutations
PMID 17704260: genotype-phenotype correlation in CFC/NS including KRAS V14I
PMID 18958496: V14I in Taiwan Noonan syndrome patients
PMID 19020799: V14I in Korean Noonan syndrome patients
ClinVar: 19 clinical laboratories classify as Pathogenic
ClinGen RASopathy EP classifies as Pathogenic

Sources

PMID:16474405 ↗clinvar ↗

PM1 ModerateVal14 is located within the P-loop (phosphate-binding loop), an approved functional domain per the VCEP supplemental PM1 materials (HRAS residues 10-17; homologous in KRAS per Group 1: HRAS, KRAS, NRAS). The P-loop is critical for GTP/GDP binding and is a well-established mutational hotspot in RAS proteins. The variant is absent from population databases at meaningful frequency with no benign variation at this residue. Details ▾Hide ▴

Evidence considered

VCEP PM1 domains document confirms P-loop (residues 10-17) as approved functional domain
Val14 is within the P-loop
which contacts the nucleotide via backbone atoms
Statistical significance at this residue per cancerhotspots.org

Sources

vcep_alignment_with_pm1_domains_pptx

PM6 ModeratePMID 16474405 reports KRAS V14I as a de novo germline mutation in a patient with Noonan syndrome and no family history. Paternity and maternity confirmation are not documented in the available abstract. Per VCEP PM6 moderate rule, confirmed de novo without confirmation of paternity and maternity qualifies at moderate strength. Details ▾Hide ▴

Evidence considered

PMID 16474405: de novo germline KRAS V14I mutation in Noonan syndrome proband
paternity/maternity not confirmed

Still missing

Full text of PMID 16474405 not available for verification

Sources

PMID:16474405 ↗

PP2 SupportingThe VCEP explicitly states that PP2 is applicable to all RASopathy genes described and curated in the framework. KRAS is a RASopathy gene with a low rate of benign missense variation, and missense variants are a common mechanism of disease in RASopathies. Details ▾Hide ▴

Evidence considered

VCEP states PP2 is applicable to all RASopathy genes

Sources

cspec ↗

PP3 SupportingMultiple lines of computational evidence support a deleterious effect. REVEL score is 0.803 (pathogenic range). BayesDel score is 0.29 (borderline but consistent with deleterious). SpliceAI predicts no significant splice impact (max delta 0.01). The variant substitutes a highly conserved valine with isoleucine in the P-loop, a critical functional domain. Details ▾Hide ▴

Evidence considered

REVEL score 0.803 (deleterious)
BayesDel score 0.289645 (borderline deleterious)
SpliceAI max delta 0.01 (no splicing impact)
V14 is conserved across RAS isoforms

Sources

revelbayesdelspliceai ↗

PP5 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic. Details ▾Hide ▴

Evidence considered

VCEP marks PP5 as Not Applicable
ClinVar expert panel classification

Sources

cspec ↗clinvar ↗

Not met · 12 · evaluated, threshold not reached

PS1 No different nucleotide change at codon 14 (Val) has been established as pathogenic per VCEP criteria. No PS1 comparator exists. Details ▾Hide ▴

Evidence considered

No same-codon pathogenic variant identified to serve as PS1 comparator

PS2 The VCEP PS2 strong rule requires de novo occurrence with paternity confirmed. PMID 16474405 reports V14I as a de novo germline mutation in Noonan syndrome, but paternity confirmation is not documented in the available abstract and full text is not available. Evidence is assessed under PM6 instead. Details ▾Hide ▴

Evidence considered

PMID 16474405 abstract reports de novo germline KRAS V14I mutation in Noonan syndrome
paternity not confirmed

Still missing

Full text of PMID 16474405 not available to verify paternity confirmation

Sources

PMID:16474405 ↗

PM2 The VCEP PM2 rule requires the variant to be completely absent from all population databases. gnomAD v4.1 reports 2 alleles out of 1,612,846 (AF = 0.00012%) in the European (non-Finnish) population. Although gnomAD v2.1 and gnomAD-Canada show zero alleles, the presence in gnomAD v4.1 violates the VCEP requirement for complete absence. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 0/249
502 alleles (absent)
gnomAD v4.1: 2/1
612
846 alleles (AF = 0.00012%)
2 alleles in European (non-Finnish)
gnomAD-Canada: absent
VCEP PM2 requires complete absence from all population databases

Sources

gnomad_v4 ↗

PP1 No segregation data are available for this variant. The VCEP PP1 rule requires at least three informative meioses for the supporting level. No family studies with segregation analysis were identified. Details ▾Hide ▴

Evidence considered

No segregation data available

Still missing

Segregation data needed to apply PP1

BA1 The VCEP BA1 threshold is allele frequency ≥0.05%. gnomAD v2.1 reports 0/249,502 alleles (AF=0). gnomAD v4.1 reports 2/1,612,846 alleles (AF=0.00012%). Both are well below the 0.05% threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF = 0% (0/249
502)
gnomAD v4.1: AF = 0.00012% (2/1
612
846)
VCEP BA1 threshold: ≥0.05%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 The VCEP BS1 threshold is allele frequency ≥0.025%. The observed frequency in gnomAD v4.1 (0.00012%) is well below this threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF = 0%
gnomAD v4.1: AF = 0.00012%
VCEP BS1 threshold: ≥0.025%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 The VCEP BS2 rule states that general population data should not be used for this criterion due to variable expressivity and severity in RASopathies. Clinical laboratories are encouraged to accumulate more than 3 instances of well-phenotyped family members before applying. No such evidence is available. Details ▾Hide ▴

Evidence considered

No well-phenotyped unaffected family members documented

BS3 VCEP-approved functional studies (PMID 20949621) demonstrate a damaging effect for KRAS V14I, with increased nucleotide exchange, GTP-bound accumulation, and increased downstream signaling. BS3 requires functional studies showing no damaging effect, which is contradicted by the available evidence. Details ▾Hide ▴

Evidence considered

V14I shows gain-of-function in approved functional assays
BS3 criteria not satisfied

Sources

PMID:20949621 ↗

BS4 The VCEP BS4 rule requires only one informative meiosis showing lack of segregation with disease. No such data are available for KRAS V14I. Details ▾Hide ▴

Evidence considered

No segregation data showing non-segregation with disease

BP2 No evidence of this variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴

Evidence considered

No trans/cis evidence available

BP4 Multiple lines of computational evidence (REVEL 0.803, BayesDel 0.29) suggest a deleterious impact on the gene product. BP4 requires evidence suggesting no impact, which is contradicted by the available in silico data. Details ▾Hide ▴

Evidence considered

REVEL score 0.803 supports deleterious effect
BayesDel score 0.29 is borderline but does not support absence of impact

Sources

revelbayesdel

BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease. Details ▾Hide ▴

Evidence considered

No alternate molecular basis identified

Not assessed · 1 · no assessment recorded

PS5 No evidence of the same nucleotide change detected independently or in trans configuration was identified for this variant. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 VCEPPVS1 is explicitly designated as Not Applicable by the ClinGen RASopathy VCEP (Version 1.0). Details ▾Hide ▴

Evidence considered

CSPEC/VCEP framework marks PVS1 as Not Applicable for KRAS

Sources

cspec ↗

PM5 N/AVal14 is within the P-loop, a designated PM1 mutational hotspot. Per VCEP PM5 rule, PM5 should not be used as an independent criterion in conjunction with PM1 when the residue is explicitly designated as a mutational hot-spot. No same-residue pathogenic missense comparator variants were identified. Details ▾Hide ▴

Evidence considered

VCEP PM5 rule prohibits independent use with PM1 for hotspot residues

Sources

cspec ↗

PP4 VCEPPP4 is explicitly designated as Not Applicable by the ClinGen RASopathy VCEP. Proband counting is instead handled under PS4. Details ▾Hide ▴

Evidence considered

VCEP marks PP4 as Not Applicable for RASopathies

Sources

cspec ↗

BP1 N/AThe VCEP BP1 rule applies to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, entire gene or multi-exon deletion) in genes without established LOF correlation to disease. KRAS V14I (p.Val14Ile) is a missense variant and does not meet the BP1 criteria for truncating variants. Details ▾Hide ▴

Evidence considered

V14I is missense
not truncating
BP1 applies only to truncating variants per VCEP

Sources

cspec ↗

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. NM_033360.4:c.40G>A is a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is explicitly designated as Not Applicable by the ClinGen RASopathy VCEP per recommendation of the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

Evidence considered

VCEP marks BP6 as Not Applicable

Sources

cspec ↗

BP7 N/ABP7 applies to synonymous (silent) variants or intronic/non-coding variants. NM_033360.4:c.40G>A is a missense variant (p.Val14Ile) and is not eligible for BP7. Details ▾Hide ▴

Evidence considered

V14I is missense
not synonymous

Identifiers

Gene: KRAS
Transcript: NM_033360.4
Coding (HGVS c.): NM_033360.4:c.40G>A
Protein (HGVS p.): NP_203524.1:p.(Val14Ile)
GRCh38: chr12:25245345 C>T
GRCh37: chr12:25398279 C>T
ClinVar: 12589
COSMIC: COSV55501342

Gene diagram

Every interpreted variant in KRAS, mapped onto the exon structure of NM_033360.4. Select a row to find it on the plot.

KRASNM_033360.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in KRAS — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 2 / 1,612,846 alleles AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07

gnomAD v2.1 0 / 249,502 alleles AF 0 · 0 homozygotes

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.2e-06 · 2 / 1,612,846 alleles · 0 hom · FAF 2.8e-07

European (non-Finnish)2 / 1,179,292

1.7e-06

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 0 · 0 / 249,502 alleles · 0 hom

No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.24004e-06; MAF= 0.00012%, 2/1612846 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69593e-06; MAF= 0.00017%, 2/1179292 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +14 bp

0.010

SpliceAI acceptor gainat -491 bp

0.000

SpliceAI donor lossat -71 bp

0.000

SpliceAI donor gainat +153 bp

0.000

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.000

Other predictors

REVEL: 0.803
BayesDel: 0.290

How the predictions were used

Evidence considered

REVEL score 0.803 (deleterious)
BayesDel score 0.289645 (borderline deleterious)
SpliceAI max delta 0.01 (no splicing impact)
V14 is conserved across RAS isoforms

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL score 0.803 supports deleterious effect
BayesDel score 0.29 is borderline but does not support absence of impact

Sources

revelbayesdel

BP7 N/ABP7 applies to synonymous (silent) variants or intronic/non-coding variants. NM_033360.4:c.40G>A is a missense variant (p.Val14Ile) and is not eligible for BP7. Details ▾Hide ▴

Evidence considered

V14I is missense
not synonymous

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.803. BayesDel score = 0.289645.

8 paper records listed. 3 cited in the classification.

Cited in the classification

Germline KRAS mutations cause Noonan syndrome.

Schubbert S et al. · 2006 Mar

First report of germline KRAS mutations in Noonan syndrome. V14I, T58I, and D153V were identified as de novo heterozygous mutations in PTPN11 mutation-negative Noonan syndrome patients. V14I and T58I reduce GTPase activity, resulting in increased RAS signaling.
→ PS4 → PM6 Names this variant
PMID 16474405 ↗
Source detail

We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V in five PTPN11-negative individuals with Noonan syndrome.

Location Abstract
Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction.

Gelb BD et al. · 2006 Oct 15

Review article discussing KRAS mutations in Noonan syndrome. Summarizes that V14I and T58I mutant KRAS proteins in the P-loop and Switch II have less GTPase activity than wild-type KRAS but more than oncogenic G12D, reducing RAS inactivation and resulting in increased signaling.
→ PS4 Names this variant
PMID 16987887 ↗
Source detail

Two mutant KRAS proteins, V14I and T58I, affecting the P-loop and Switch II in the G domain, respectively, have less GTPase activity, basally and after stimulation with a GAP protein, than wild-type KRAS but more than the oncogenic G12D.

Location New Noonan syndrome gene discovery–KRAS section, paragraph 3
Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders.

Gremer L et al. · 2011 Jan

Comprehensive biochemical characterization of 10 germline KRAS mutants including V14I. KRAS V14I demonstrated approximately 30-fold increase in intrinsic and GEF-catalyzed nucleotide exchange, accumulation in GTP-bound active state in COS-7 cells, and increased phosphorylation of MEK, ERK, and AKT. Classified as Class B mutant with fast nucleotide exchange as the primary pathogenic mechanism.
→ PS3 Names this variant
PMID 20949621 ↗
Source detail

The most significant effect was an increase in dissociation of the fluorescently labeled GDP (mantGDP) from RAS mutants by almost 30-fold in the case of p.V14I and p.Q22E, and more than 60-fold in p.F156L.

Location Results throughout; Table 1; Figures 2-5; Discussion Class B

Context COS-7 cells transiently transfected with KRAS variants; recombinant HRAS proteins expressed in E. coli; GST pull-down assays using RAF1-RBD; fluorescence-based nucleotide exchange and GTP hydrolysis assays

Other recorded publications

Clinical and Functional Characterization of Atypical KRAS/NRAS Mutations in Metastatic Colorectal Cancer.

Clinical and functional characterization of atypical KRAS/NRAS mutations in metastatic colorectal cancer using in vitro cell-based assays. KRAS V14I was not tested or mentioned in this paper, which focuses on somatic colorectal cancer mutations.
Does not name this variant
PMID 34117033 ↗
Biochemical and functional characterization of germ line KRAS mutations.

Schubbert S et al. · 2007

Biochemical and functional characterization of three germline KRAS mutants: P34R, D153V, and F156L found in Noonan syndrome and CFC syndrome. The V14I variant is mentioned only in citing prior work by Schubbert et al. 2006 as a previously characterized NS-associated mutant; V14I was not directly tested in this study.
Does not name this variant
PMID 17875937 ↗
Quoted passage
NS-associated K-Ras proteins (V14I and T58I K-Ras) are gain-of-function alleles that are less activated than oncogenic G12D K-Ras by a variety of biochemical and functional criteria (24).
Introduction; Table 1
Spectrum of mutations in Noonan syndrome and their correlation with phenotypes.

Lee BH et al. · 2011

No paper-specific finding is recorded.

PMID 21784453 ↗
Endometrial cancer: a review and current management strategies: part I.

No paper-specific finding is recorded.

PMID 24905773 ↗
2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).

No paper-specific finding is recorded.

PMID 25173338 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 2 / 1,612,846 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗

ClinVar 19 Pathogenic · 1 pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (19 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 12589)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.803. BayesDel score = 0.289645.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55501342, n = 46 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.