rs727503109
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_004985.5(KRAS):c.108A>G(p.Ile36Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
KRAS
NM_004985.5 missense
NM_004985.5 missense
Scores
9
7
3
Clinical Significance
Conservation
PhyloP100: 0.810
Genes affected
KRAS (HGNC:6407): (KRAS proto-oncogene, GTPase) This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Alternative splicing leads to variants encoding two isoforms that differ in the C-terminal region. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a chain GTPase KRas, N-terminally processed (size 184) in uniprot entity RASK_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_004985.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.908
PP5
Variant 12-25245277-T-C is Pathogenic according to our data. Variant chr12-25245277-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 163768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-25245277-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KRAS | NM_004985.5 | c.108A>G | p.Ile36Met | missense_variant | 2/5 | ENST00000311936.8 | NP_004976.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KRAS | ENST00000311936.8 | c.108A>G | p.Ile36Met | missense_variant | 2/5 | 1 | NM_004985.5 | ENSP00000308495.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Feb 23, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 23, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18470943, 21784453, 24803665, 25525159, 18958496, 29493581, 17056636, 30586318, 32240795, 35158933, 17211612, 27104176, 37434678, 36066546, 37065036, 38339343) - |
RASopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 01, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 36 of the KRAS protein (p.Ile36Met). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. ClinVar contains an entry for this variant (Variation ID: 163768). This missense change has been observed in individual(s) with RASopathies spectrum (PMID: 17056636, 18958496, 21784453; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 25, 2018 | Variant summary: KRAS c.108A>G (p.Ile36Met) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 237482 control chromosomes (gnomAD). c.108A>G has been reported in the literature in individuals affected with Noonan Syndrome (Zenker 2007, Lo 2009, Lee 2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported; though an in vitro study demonstrated that substitutions of Ile36 caused severe impairment in Ras protein function, indicating the importance of this amino acid residue (Chung 1993). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic (1x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 15, 2018 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Cardiofaciocutaneous syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | - | - - |
KRAS-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 04, 2023 | The KRAS c.108A>G variant is predicted to result in the amino acid substitution p.Ile36Met. This variant has been reported as a recurrent finding in individuals with Noonan syndrome (Zenker et al. 2007. PubMed ID: 17056636; Lo et al. 2009. PubMed ID: 18958496; Lee et al. 2011. PubMed ID: 21784453). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 01, 2017 | The p.I36M pathogenic mutation (also known as c.108A>G), located in coding exon 1 of the KRAS gene, results from an A to G substitution at nucleotide position 108. The isoleucine at codon 36 is replaced by methionine, an amino acid with similar properties. This variant has been reported in two unrelated individuals with clinical diagnoses of Noonan syndrome (Zenker M et al. J Med Genet. 2007;44(2):131-5; Lo FS et al. Eur J Pediatr. 2009;168(8):919-23). This amino acid substitution resulted in decreased GAP activation in vitro (Chung HH et al. Proc Natl Acad Sci U S A. 1993;90(21):10145-9). In addition, this mutation has been determined by our laboratory to be the result of a de novo event in one family in the setting of new disease. Based on the supporting evidence, p.I36M is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D;T;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;M;.
PrimateAI
Pathogenic
T
PROVEAN
Benign
N;D;N;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
P;.;D;.
Vest4
MutPred
Gain of catalytic residue at E31 (P = 0.0146);Gain of catalytic residue at E31 (P = 0.0146);Gain of catalytic residue at E31 (P = 0.0146);Gain of catalytic residue at E31 (P = 0.0146);
MVP
MPC
2.4
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at