Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_004985.5 | MANE Select | 5306 nt | 191–757 |
| NM_004985.4 | Alternative | 5765 nt | 193–759 |
| NM_004985.3 | Alternative | 5312 nt | 182–748 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe Thr58Ile variant in KRAS has been previously reported in at least one fetus, one infant, and one child with clinical features of Noonan syndrome (Schubbert 2006, Houweling 2010, Croonen 2013, LMM-unpublished data). In both the fetus and the infant, the variant was reported to be de novo (Schubbert 2006, Croonen 201 3). Functional studies show that this variant impacts the protein's GTPase activ ity and leads to overall enhanced downstream signaling (Schubbert 2006, Gremer 2 010). In addition, this variant was absent from large population studies. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp gm.partners.org/LMM).
The c.173C>T (p.Thr58Ile) variant in KRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6_Strong; PMID 23321623, 20112233, 16921267, 16474405, 22488832, 18247425, 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Thr58Ile variant may impact protein function (PS3; PMID: 23321623, 20949621, 16921267). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of KRAS (PM1; PMID 29493581). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr58Ile variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PM2, PM1, PP2, PP3.
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 58 of the KRAS protein (p.Thr58Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome and Costello syndrome and Noonan syndrome (PMID: 16474405, 17704260, 19396835, 20186801). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12588). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt KRAS function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 16474405, 20949621). For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Error in OpenAI Consolidation. OncoKB: KRAST58IKRAST58ISomaticNCBI Gene:3845|Show additional gene information Variant OverviewKRAS, a GTPase which functions as an upstream regulator of the MAPK pathway, is frequently mutated in various cancer types including lung, colorectal and pancreatic cancers.The KRAS T58I mutation is likely oncogenic.Hide mutation effect description The KRAS T58I mutation is located in the catalytic G-domain of the protein. This mutation has been found in leukemia and lung cancer (PMID: 28572459). Expression of this mutation in vitro demonstrated that it is activating as measured by increased protein and pathway activation compared to wildtype (PMID: 20949621). In vitro studies demonstrated that this mutation confers resistance to the BCR-ABL tyrosine kinase inhibitors, imatinib and dasatinib, in BCR-ABL-expressing murine leukemia cells as measured by sustained proliferation in the presence of the drug. In a case study, one patient with chronic myeloid leukemia that acquired this mutation developed resistance to imatinib despite initially responding to the drug (PMID: 18509354). JAX-CKB: No results found
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 61 bp |
| Donor Loss (DL) | 0.0 | -15 bp |
| Acceptor Gain (AG) | 0.0 | 225 bp |
| Donor Gain (DG) | 0.03 | -5 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PS3 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PM2 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PP5 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
BP4 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)