rs727503109

Variant names:

• chr12-25245277-T-C
• rs727503109
• NM_004985.5:c.108A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I36K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.810
• Publications: 37 publications found

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]

KRAS Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• linear nevus sebaceous syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a chain GTPase KRas, N-terminally processed (size 184) in uniprot entity RASK_HUMAN there are 82 pathogenic changes around while only 0 benign (100%) in NM_004985.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 65 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 2.3177 (below the threshold of 3.09). Trascript score misZ: 3.0857 (below the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 2, Noonan syndrome 3, Noonan syndrome, Costello syndrome, linear nevus sebaceous syndrome.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.108A>G	p.Ile36Met	missense_variant	Exon 2 of 5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.108A>G	p.Ile36Met	missense_variant	Exon 2 of 5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Feb 23, 2018

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Oct 23, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 25, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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. -

Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1

Feb 15, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiofaciocutaneous syndrome 1 Pathogenic:1

-

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KRAS-related disorder Pathogenic:1

Nov 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 01, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	.;.;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T;D;T;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.2	M;.;M;.
PhyloP100		0.81
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.4	N;D;N;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.93	P;.;D;.
Vest4		0.86
MutPred		0.77		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		0.96
MPC		2.4
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.95
gMVP		0.88
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727503109; hg19: chr12-25398211; COSMIC: COSV55721142;