KRASc.183A>CLikely pathogenic

Print report

Variant interpretation report

KRAS c.183A>C, p.(Gln61His)

NM_033360.4:c.183A>C NP_203524.1:p.(Gln61His) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

Likely pathogenic.A likely 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) · 2 supporting (pathogenic)
Expert rules: ClinGen KRAS VCEP v1.0
Other laboratories (ClinVar): 3 Pathogenic · 2 Uncertain significance
Pipeline record: 24 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PM5 (strong): Multiple different pathogenic missense variants have been previously reported at codon 61 of KRAS in association with germline RASopathies. KRAS c.182A>G (p.Gln61Arg, Q61R) and KRAS c.181C>A (p.Gln61Lys, Q61K) are established pathogenic variants in Noonan syndrome and cardio-facio-cutaneous syndrome. The amino acid change from glutamine (uncharged polar) to histidine (positively charged basic) at position 61 is concordant with the pathogenic direction of known codon 61 substitutions, all of which impair GTPase activity. The VCEP PM5 threshold of ≥2 different pathogenic missense changes at the same residue is satisfied; PM5_Strong also applies to analogous residues in Group 1 genes (HRAS, NRAS, KRAS). Note: the VCEP instructs that PM5 should not be used independently with PM1 if the residue is explicitly designated a mutational hotspot; since residue 61 is not explicitly listed in VCEP PM1 domain material, this co-use restriction does not apply.
PP2 (supporting): The RASopathy VCEP explicitly states that PP2 is applicable to all RASopathy genes described and curated in the framework, including KRAS. This is a missense variant in a gene where missense variants are a common mechanism of disease and the gene has a low rate of benign missense variation.
PP3 (supporting): Multiple lines of computational evidence support a deleterious effect: REVEL score of 0.644 (above typical 0.5 threshold), a statistically significant mutational hotspot at residue 61, and an oncogenic classification by OncoKB. The variant has been recurrently observed in somatic cancers (COSMIC, n=447). SpliceAI predicts no significant splice impact (max delta=0.12). The RASopathy VCEP allows PP3 at Supporting strength when multiple computational lines support a deleterious effect.

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: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PM5Strong

PM5 · strong

Multiple different pathogenic missense variants have been previously reported at codon 61 of KRAS in association with germline RASopathies. KRAS c.182A>G (p.Gln61Arg, Q61R) and KRAS c.181C>A (p.Gln61Lys, Q61K) are established pathogenic variants in Noonan syndrome and cardio-facio-cutaneous syndrome. The amino acid change from glutamine (uncharged polar) to histidine (positively charged basic) at position 61 is concordant with the pathogenic direction of known codon 61 substitutions, all of which impair GTPase activity. The VCEP PM5 threshold of ≥2 different pathogenic missense changes at the same residue is satisfied; PM5_Strong also applies to analogous residues in Group 1 genes (HRAS, NRAS, KRAS). Note: the VCEP instructs that PM5 should not be used independently with PM1 if the residue is explicitly designated a mutational hotspot; since residue 61 is not explicitly listed in VCEP PM1 domain material, this co-use restriction does not apply.

PP2Supporting

PP2 · supporting

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

PP3Supporting

PP3 · supporting

Multiple lines of computational evidence support a deleterious effect: REVEL score of 0.644 (above typical 0.5 threshold), a statistically significant mutational hotspot at residue 61, and an oncogenic classification by OncoKB. The variant has been recurrently observed in somatic cancers (COSMIC, n=447). SpliceAI predicts no significant splice impact (max delta=0.12). The RASopathy VCEP allows PP3 at Supporting strength when multiple computational lines support a deleterious effect.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely 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: PM5 strong, PP2 supporting, PP3 supporting; combination = 1 strong + 2 supporting, which maps to Likely 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

Not recorded

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

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.97918e-06; MAF= 0.00040%, 1/251308 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.92457e-05; MAF= 0.00992%, 1/10076 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

0.120 maximum delta

Recorded SpliceAI maximum delta score: 0.120. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

5 reported laboratory submissions

3 Pathogenic · 2 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗

Functional evidence

Statement recorded

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

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

447 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55498802, n = 447 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.

26 criteria with recorded statuses: 3 met · 15 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 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_033360.4:c.183A>C (p.Gln61His) is a missense variant in KRAS, a gene in which gain-of-function missense variants cause RASopathies including Noonan syndrome and cardio-facio-cutaneous syndrome.

Multiple different pathogenic missense variants have been established at codon 61 in germline RASopathies (p.Gln61Arg and p.Gln61Lys), satisfying PM5 at Strong strength under the RASopathy VCEP. The Gln61His substitution is concordant with the known pathogenic direction of codon 61 changes which impair GTPase activity.

PP2 is applied at Supporting strength per VCEP specification, as PP2 is applicable to all RASopathy genes including KRAS.

PP3 is applied at Supporting strength based on multiple computational lines of evidence: REVEL score 0.644 predicts a deleterious effect, residue 61 is a statistically significant mutational hotspot, and the variant is classified as Oncogenic (gain-of-function) by OncoKB.

Variant-specific functional evidence from PMID:20147967 demonstrates that KRAS Q61H transforms NIH3T3 cells in focus formation assays and is present in the active GTP-bound conformation. PMID:25705018 shows Q61H produces a 5-6 fold increase in GTP-bound KRAS and promotes anchorage-independent growth in MCF10A isogenic cells. These studies provide strong functional support for a gain-of-function effect but do not meet the strict VCEP requirement for PS3 (must use VCEP-approved functional study publications).

PM1 could not be applied because residue 61 falls in Switch II (residues 60-76), which is not explicitly listed in the available VCEP PM1 domain supplemental material (only P-loop 10-17 and Switch I 25-40 are listed). Human review is recommended as Switch II is a well-established critical functional domain and residue 61 is a documented mutational hotspot.

PM2 is not met because the variant is present in gnomAD v2.1 at extremely low frequency (1/251,308 alleles) rather than being completely absent from all population databases as required by the VCEP.

PVS1 is not applicable per VCEP designation and because this is a missense variant rather than a null variant. PS4, PS2, PM6, PP1, BS2, BS4, BP2, and BP5 could not be assessed due to absence of proband-level clinical data, de novo testing, or segregation analysis.

Met · 3

PM5 StrongMultiple different pathogenic missense variants have been previously reported at codon 61 of KRAS in association with germline RASopathies. KRAS c.182A>G (p.Gln61Arg, Q61R) and KRAS c.181C>A (p.Gln61Lys, Q61K) are established pathogenic variants in Noonan syndrome and cardio-facio-cutaneous syndrome. The amino acid change from glutamine (uncharged polar) to histidine (positively charged basic) at position 61 is concordant with the pathogenic direction of known codon 61 substitutions, all of which impair GTPase activity. The VCEP PM5 threshold of ≥2 different pathogenic missense changes at the same residue is satisfied; PM5_Strong also applies to analogous residues in Group 1 genes (HRAS, NRAS, KRAS). Note: the VCEP instructs that PM5 should not be used independently with PM1 if the residue is explicitly designated a mutational hotspot; since residue 61 is not explicitly listed in VCEP PM1 domain material, this co-use restriction does not apply. Details ▾Hide ▴

Evidence considered

Q61R (c.182A>G) and Q61K (c.181C>A) are established pathogenic germline RASopathy variants at codon 61
Q61H amino acid change is concordant with known pathogenic substitutions at this residue
VCEP Group 1 analog rule (HRAS/NRAS/KRAS) supports cross-gene PM5 application

Sources

clinvar ↗cspec ↗

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

Evidence considered

VCEP rule: PP2 applicable to all RASopathy genes including KRAS
Missense variant in a gain-of-function disease mechanism gene

Sources

cspec ↗

PP3 SupportingMultiple lines of computational evidence support a deleterious effect: REVEL score of 0.644 (above typical 0.5 threshold), a statistically significant mutational hotspot at residue 61, and an oncogenic classification by OncoKB. The variant has been recurrently observed in somatic cancers (COSMIC, n=447). SpliceAI predicts no significant splice impact (max delta=0.12). The RASopathy VCEP allows PP3 at Supporting strength when multiple computational lines support a deleterious effect. Details ▾Hide ▴

Evidence considered

REVEL 0.644 supports deleterious effect
Residue 61 is a statistically significant hotspot (cancerhotspots.org)
OncoKB: Oncogenic
gain-of-function
COSMIC: recurrent somatic variant (n=447)
BayesDel 0.145 (below typical damaging threshold but not contradictory)

Sources

revelbayesdeloncokb ↗spliceai ↗

Not met · 15 · evaluated, threshold not reached

PS1 No evidence that this exact nucleotide change or the same amino acid change arising from a different nucleotide substitution has been previously established as pathogenic under the RASopathy VCEP criteria. Details ▾Hide ▴

Evidence considered

No prior pathogenic classification per VCEP criteria identified for this exact amino acid change at codon 61

Still missing

No prior VCEP-level classification of Q61H or any other nucleotide change producing Gln61His

PS2 No de novo occurrence data reported in the case materials or literature. The RASopathy VCEP requires confirmed paternity for PS2_Strong and ≥2 independent occurrences for PS2_Very_Strong. Details ▾Hide ▴

Evidence considered

No de novo events reported

Still missing

Absence of de novo testing data for this proband

PS4 Insufficient independent proband count data to meet VCEP thresholds (≥1 supporting, ≥3 moderate, ≥5 strong). While ClinVar contains submissions with classifications of Pathogenic and Likely pathogenic, the proband-level clinical data required for PS4 proband counting is not available. Details ▾Hide ▴

Evidence considered

ClinVar submissions present but no proband-level phenotype counts available

Still missing

Proband counting requires individual clinical case data with phenotype confirmation

Sources

clinvar ↗

PM1 The RASopathy VCEP PM1 rule references supplemental material for approved functional domains and residues. The only supplemental domain material available (Alignment-with-PM1-domains.pptx) lists P-loop (HRAS residues 10-17) and Switch I (HRAS residues 25-40) as approved PM1 domains. Residue 61 is located in the Switch II region (residues 60-76), which is not explicitly listed in the VCEP-approved PM1 domains. Despite residue 61 being a statistically significant mutational hotspot (cancerhotspots.org) and a critical functional residue for GTP hydrolysis, it falls outside the VCEP-defined PM1 boundaries. Details ▾Hide ▴

Evidence considered

Residue 61 is a statistically significant hotspot
Residue 61 is in Switch II
a critical functional domain for GTPase activity
VCEP PM1 supplemental material does not include residue 61 in its approved domain list (lists P-loop 10-17 and Switch I 25-40 only)

Still missing

VCEP supplemental material approval status of Switch II (residues 60-76) as a PM1 domain is unclear from available materials
the PPTX may not be exhaustive

Sources

cspec ↗vcep_alignment_with_pm1_domains_pptx

PM2 The RASopathy VCEP requires the variant to be completely absent from all population databases for PM2_Moderate. This variant is present in gnomAD v2.1 at a very low frequency (1/251,308 alleles; AF=3.98e-06) in the Ashkenazi Jewish subpopulation. Because it is not completely absent, PM2 cannot be applied under the VCEP rule. Details ▾Hide ▴

Evidence considered

Present in gnomAD v2.1: 1/251
308 alleles (AF=3.98e-06)
Ashkenazi Jewish subpopulation (1/10
076)
Absent from gnomAD v4.1
VCEP PM2 rule requires complete absence from all population databases

Sources

gnomad_v2 ↗

PM6 No de novo occurrence data reported. The RASopathy VCEP requires confirmed de novo (without paternity/maternity confirmation for PM6_Moderate) or ≥2 independent PM6 occurrences for PM6_Strong. Details ▾Hide ▴

Evidence considered

No de novo data available

Still missing

No de novo testing or reporting for this variant

PP1 No segregation data available. The RASopathy VCEP requires at least 3 informative meioses for PP1_Supporting, ≥5 for PP1_Moderate, and ≥7 for PP1_Strong. No family studies or segregation analysis were identified. Details ▾Hide ▴

Still missing

No family segregation data

BA1 The RASopathy VCEP BA1 threshold is an allele frequency ≥0.05%. The variant allele frequency in gnomAD v2.1 is 3.98e-06 (0.0004%), well below the BA1 cutoff. Absent from gnomAD v4.1. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=3.98e-06 (0.0004%) << BA1 threshold of 0.05%
Absent from gnomAD v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 The RASopathy VCEP BS1 threshold is an allele frequency ≥0.025%. The variant allele frequency in gnomAD v2.1 is 3.98e-06 (0.0004%), far below the BS1 cutoff. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=3.98e-06 (0.0004%) << BS1 threshold of 0.025%

Sources

gnomad_v2 ↗

BS2 The RASopathy VCEP states that general population data should not be used for BS2 due to variable expressivity and severity of RASopathies. Requires >3 instances of well-phenotyped family members. No such data available. Details ▾Hide ▴

Evidence considered

VCEP BS2 requires well-phenotyped family members
not population data
No family phenotype data available

Still missing

Requires >3 well-phenotyped family member observations

Sources

cspec ↗

BS3 BS3 requires well-established functional studies showing no damaging effect. The available functional data (PMID:20147967, PMID:25705018) convincingly demonstrate a gain-of-function effect for Q61H (increased GTP-bound RAS, focus formation, anchorage-independent growth), which is opposite to the requirement for BS3. The VCEP-approved functional assays for KRAS are designated PS3_Supporting; BS3 is not applicable for KRAS under the VCEP approved assays. Details ▾Hide ▴

Evidence considered

Q61H shows gain-of-function
not benign effect
VCEP approved KRAS functional assays are designated PS3_Supporting / BS3_NA

Sources

PMID:20147967 ↗PMID:25705018 ↗

BS4 No segregation data available. The RASopathy VCEP requires only one informative meiosis but no family studies were identified. Details ▾Hide ▴

Still missing

No segregation analysis available

BP2 No evidence that this variant has been observed in trans with a pathogenic variant (for dominant disorder) or in cis with a pathogenic variant. No such data was identified in the case materials or literature. Details ▾Hide ▴

Still missing

No trans/cis phase data with other pathogenic variants

BP4 The RASopathy VCEP requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL score of 0.644 indicates a predicted deleterious effect, not absence of impact. While SpliceAI (max delta=0.12) predicts no splice impact, the overall computational evidence points toward a damaging effect rather than no impact. BP4 cannot be applied when computational evidence supports pathogenicity. Details ▾Hide ▴

Evidence considered

REVEL 0.644 predicts damaging
contradicting BP4
SpliceAI 0.12 predicts no splice impact
BayesDel 0.145 is below typical damaging threshold but does not independently establish 'no impact'

Sources

revelspliceai ↗bayesdel

BP5 No evidence that this variant has been observed in a case with an alternate molecular basis for disease. No such data was identified. Details ▾Hide ▴

Still missing

No alternate molecular diagnosis identified in any case harboring this variant

Not assessed · 1 · no assessment recorded

PS3 The RASopathy VCEP restricts PS3 to Strong strength using VCEP-approved functional studies (RAS Activation Assay, MEK Activation Assay, ERK Activation Assay). The VCEP-approved KRAS functional studies (PMID: 20949621, 23059812) did not test p.Gln61His. However, substantial variant-specific functional evidence exists from non-VCEP-approved studies: PMID:20147967 demonstrated Q61H transforms NIH3T3 cells in focus formation assays and activates GTP-bound RAS; PMID:25705018 showed Q61H produces a 5-6 fold increase in GTP-bound KRAS and promotes anchorage-independent growth in MCF10A isogenic cells. This functional evidence supports a gain-of-function effect consistent with RASopathy pathogenesis but cannot be assigned PS3 under strict VCEP rules without submission to the expert panel for approval. Details ▾Hide ▴

Evidence considered

VCEP-approved KRAS functional assay types exist (RAS/MEK/ERK Activation
PS3_Supporting for KRAS)
PMID:20147967: Q61H transforms NIH3T3 (focus formation)
activates GTP-bound RAS
PMID:25705018: Q61H shows 5-6x increased GTP-KRAS
anchorage-independent growth in MCF10A

Still missing

Functional studies for Q61H are not from VCEP-approved publications
require submission to RASopathy VCEP for PS3 approval

Sources

PMID:20147967 ↗PMID:25705018 ↗cspec ↗

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

PVS1 VCEPThe ClinGen RASopathy VCEP designates PVS1 as Not Applicable. The variant is a missense substitution (c.183A>C, p.Gln61His), not a null variant eligible for PVS1 under the generic ClinGen SVI decision tree. Details ▾Hide ▴

Evidence considered

VCEP framework declares PVS1 Not Applicable for RASopathies
variant is missense
not a null allele

Sources

cspec ↗

PP4 VCEPThe RASopathy VCEP designates PP4 as Not Applicable for this VCEP. The VCEP instructs to use PS4 for proband counting instead. Details ▾Hide ▴

Evidence considered

VCEP PP4: Not Applicable for RASopathies

Sources

cspec ↗

PP5 VCEPThe RASopathy VCEP designates PP5 as Not Applicable for this VCEP. The VCEP does not permit the use of PP5 (reputable source classification without available evidence) in RASopathy variant interpretation. Details ▾Hide ▴

Evidence considered

VCEP PP5: Not Applicable for this VCEP

Sources

cspec ↗

BP1 N/ABP1 is designated for truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, entire gene or multi-exon deletion) in genes without established LOF correlation to disease. This is a missense variant, not a truncating variant. The VCEP further notes the RASopathy disease mechanism is gain-of-function, meaning BP1 would only apply to truncating variants in genes without LOF disease correlation. Details ▾Hide ▴

Evidence considered

Variant is missense
not truncating
BP1 not applicable to missense variants

Sources

cspec ↗

BP6 VCEPThe RASopathy VCEP designates BP6 as Not Applicable for this VCEP. The criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

Evidence considered

VCEP BP6: Not Applicable for this VCEP

Sources

cspec ↗

BP7 N/ABP7 is designated for synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. This variant is a missense substitution (c.183A>C, p.Gln61His), not a synonymous variant. Details ▾Hide ▴

Evidence considered

Missense variant
not synonymous
BP7 not applicable

PS5 N/APS5 is not defined in the RASopathy VCEP criteria. Under generic ACMG/AMP, PS5 applies when the same amino acid change results from a different nucleotide change previously established as pathogenic. This variant is being assessed for its own classification; no independent prior pathogenic assertion for Q61H from a different nucleotide change exists. Details ▾Hide ▴

Evidence considered

Not a VCEP-defined criterion
no different nucleotide change producing the same Q61H alteration identified

Identifiers

Gene: KRAS
Transcript: NM_033360.4
Coding (HGVS c.): NM_033360.4:c.183A>C
Protein (HGVS p.): NP_203524.1:p.(Gln61His)
GRCh38: chr12:25227341 T>G
GRCh37: chr12:25380275 T>G
ClinVar: 177881, 4279990, 45117
COSMIC: COSV55498802

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

—

Transcript span

—

Strand

—

Variants mapped

—

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 Allele count data not recorded

gnomAD v2.1 1 / 251,308 alleles AF 3.98e-06 · 0 homozygotes

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v2.1

AF 4e-06 · 1 / 251,308 alleles · 0 hom

Ashkenazi Jewish1 / 10,076

9.9e-05

0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +454 bp

0.000

SpliceAI acceptor gainat +7 bp

0.000

SpliceAI donor lossat +5 bp

0.120

SpliceAI donor gainat -5 bp

0.000

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.000

Other predictors

REVEL: 0.644
BayesDel: 0.145

How the predictions were used

Evidence considered

REVEL 0.644 supports deleterious effect
Residue 61 is a statistically significant hotspot (cancerhotspots.org)
OncoKB: Oncogenic
gain-of-function
COSMIC: recurrent somatic variant (n=447)
BayesDel 0.145 (below typical damaging threshold but not contradictory)

Sources

revelbayesdeloncokb ↗spliceai ↗

Evidence considered

REVEL 0.644 predicts damaging
contradicting BP4
SpliceAI 0.12 predicts no splice impact
BayesDel 0.145 is below typical damaging threshold but does not independently establish 'no impact'

Sources

revelspliceai ↗bayesdel

Evidence considered

Missense variant
not synonymous
BP7 not applicable

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.644. BayesDel score = 0.144965.

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

Recorded publications

Activating K-Ras mutations outwith 'hotspot' codons in sporadic colorectal tumours - implications for personalised cancer medicine.

KRAS Q61H was generated by site-directed mutagenesis and tested in NIH3T3 focus formation assays and RAS GTPase activation assays. Q61H produced abundant foci, confirming transforming potential, though at lower levels than codon 12 mutations. Q61H was in the active GTP-bound conformation. In transcription profiling, Q61H clustered with known activating hotspot mutations (G13D, A146T, K117N).
Names this variant
PMID 20147967 ↗
Quoted passage
SDM was carried out on the pEFHA wt K-Ras plasmid ... to generate the following K-Ras mutations: G12V, G12D, G13D, Q61H, L19F, K117N, A146T and R164Q.
Results: 'Comparison of phenotypes associated with hotspot and new K-Ras mutations'; Methods: 'Mammalian expression plasmids', 'K-Ras foci formation assays', 'Ras GTPase activating assays', 'RNA transcription profiling analysis'; Figure 3, Figure 4, Table 1
RAS oncogenes: weaving a tumorigenic web.

Comprehensive review of RAS oncogene biology covering signaling pathways, transformation mechanisms, and isoform-specific effects. Discusses oncogenic mutations at codon 61 generally (including Q61L and Q61R in specific contexts) but does not specifically mention KRAS c.183A>C (p.Gln61His).
Does not name this variant
PMID 21993244 ↗
Dragging ras back in the ring.

Review discussing the challenges of targeting RAS proteins therapeutically. No specific mention of KRAS Q61H was identified in available materials.
Does not name this variant
PMID 24651010 ↗
Comparative analysis of KRAS codon 12, 13, 18, 61, and 117 mutations using human MCF10A isogenic cell lines.

KRAS Q61H was introduced into MCF10A human mammary epithelial cells at near-physiological levels. Cells expressing Q61H showed the highest levels of GTP-bound KRAS (5-6 fold increase over control), the second-highest anchorage-independent colony formation, and increased senescence. Q61H did not confer EGF-independent proliferation or morphological changes at physiological expression.
Names this variant
PMID 25705018 ↗
Quoted passage
Unexpectedly, cells expressing the rare mutations Q61H and K117N showed the highest levels of KRAS-GTP with a 5 to 6-fold increase compared to EV-transduced cells.
Results: 'Establishment of KRAS mutant MCF10A isogenic cell lines', 'GTPase activity of KRAS mutants', 'Effects on anchorage-independent growth'; Figure 1a, Figure 2a, Figure 3c
AACR Project GENIE: Powering Precision Medicine through an International Consortium.

Describes the AACR Project GENIE consortium for sharing cancer genomic and clinical data. No specific variant data or KRAS Q61H mention found in the text. The paper focuses on consortium structure and data-sharing methodology.
Does not name this variant
PMID 28572459 ↗
National Working Group Meeting on ALK diagnostics in lung cancer.

Cooper W et al. · 2014

National Working Group Meeting report on ALK diagnostics in lung cancer. No mention of KRAS Q61H identified.
Does not name this variant
PMID 24673736 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

ACMG/AMP standards and guidelines for sequence variant interpretation. Provides the generic classification framework and evidence weighting rules. Does not mention any specific variant.
Does not name this variant
PMID 25741868 ↗
Whole-genome sequencing of patients with rare diseases in a national health system.

Turro E et al. · 2020

Whole-genome sequencing study of rare disease patients in the UK National Health Service. KRAS Q61H is not specifically discussed; the paper describes the overall diagnostic yield of WGS in a rare disease cohort. The ClinVar submission from this group (SCV001162253) classified the variant as Likely pathogenic but the publication does not provide variant-specific clinical detail.
Does not name this variant
PMID 32581362 ↗

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

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

SpliceAI Lookup Recorded maximum delta 0.120 Open source ↗

ClinVar 3 Pathogenic · 2 Uncertain significance 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

Absent from gnomAD v4.1.

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories). (ClinVarID = 177881)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.644. BayesDel score = 0.144965.

Functional

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

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55498802, n = 447 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.