chr12-25227346-C-G

Variant names:

• chr12-25227346-C-G
• rs104894359
• NM_004985.5:c.178G>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS3 PM1 PM2 PP2 PP3 PM6_Strong

This summary comes from the ClinGen Evidence Repository: The c.178G>C (p.Gly60Arg) variant in KRAS has been reported in the literature as a de novo occurrence in 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 16474404, 20949621). In vitro functional studies provide some evidence that the p.Gly60Arg variant may impact protein function (PS3; PMID 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in KRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). 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). Computational prediction tools and conservation analysis suggest that the p.Gly60Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PS3, PM2, PM1, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA273416/MONDO:0015280/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.89

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.178G>C	p.Gly60Arg	missense_variant	Exon 3 of 5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.178G>C	p.Gly60Arg	missense_variant	Exon 3 of 5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Cardiofaciocutaneous syndrome 2 Pathogenic:2

Mar 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 23, 2023

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20949621). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000012586 / PMID: 16474404) and different missense changes at the same codon (p.Gly60Ser, p.Gly60Val / ClinVar ID: VCV000012597, VCV000163766 / PMID: 19396835) Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Apr 20, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The G60R missense variant in the KRAS gene has been reported previously in association with cardio-facio-cutaneous (CFC) syndrome and observed de novo (Niihori et al., 2006; Joyce et al., 2015). The G60R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G60R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a highly conserved position within the GTP binding region. Functional in vitro studies have demonstrated that G60R results in an increase in kinase activity (MEK, ERK, and AKT) (Gremer et al., 2011). Therefore, the presence of this variant is consistent with a diagnosis of cardio-facio-cutaneous syndrome. -

Oct 12, 2017

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 29, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Inborn genetic diseases Pathogenic:1

Feb 19, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardio-facio-cutaneous syndrome Pathogenic:1

Apr 03, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.178G>C (p.Gly60Arg) variant in KRAS has been reported in the literature as a de novo occurrence in 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 16474404, 20949621). In vitro functional studies provide some evidence that the p.Gly60Arg variant may impact protein function (PS3; PMID 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in KRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). 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). Computational prediction tools and conservation analysis suggest that the p.Gly60Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PM6_Strong, PS3, PM2, PM1, PP3, PP2. -

Noonan syndrome 3 Pathogenic:1

Jun 13, 2023

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PM2, PM5, PP3, PP5 -

RASopathy Pathogenic:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 60 of the KRAS protein (p.Gly60Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 16474404, 26242988, 28650561). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12586). 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: 20949621). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	.;D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.80		Gain of catalytic residue at L56 (P = 0.1064);Gain of catalytic residue at L56 (P = 0.1064);
MVP		1.0
MPC		3.0
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894359; hg19: chr12-25380280; COSMIC: COSV55690921; COSMIC: COSV55690921;