NM_004985.5:c.468C>G

Variant names:

• chr12-25209894-G-C
• rs104894362
• NM_004985.5:c.468C>G

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_004985.5(KRAS):​c.468C>G​(p.Phe156Leu) variant causes a missense change. 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000207877: Additionally, functional in vitro studies have demonstrated that the F156L mutation results in profound activation of the MAPK pathway (Gremer et al, 2011)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F156I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.22
• Publications: 38 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]

ETFRF1 (HGNC:27052): (electron transfer flavoprotein regulatory factor 1) Involved in respiratory electron transport chain. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000207877: Additionally, functional in vitro studies have demonstrated that the F156L mutation results in profound activation of the MAPK pathway (Gremer et al, 2011).; SCV004121369: Functional studies showed that this variant led to an increase in GDP/GTP exchange and a reduction in GAP-stimulated GTPase rates (Gremer et al. 2011. PubMed ID: 20949621; Schubbert et al. 2007. PubMed ID: 17875937 ).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_004985.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-25209896-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 163758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome, linear nevus sebaceous syndrome, Noonan syndrome-like disorder with loose anagen hair, Costello syndrome, cardiofaciocutaneous syndrome 2, Noonan syndrome 3, Noonan syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 12-25209894-G-C is Pathogenic according to our data. Variant chr12-25209894-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 12595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004985.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	NM_004985.5	MANE Select	c.468C>G	p.Phe156Leu	missense	Exon 5 of 5	NP_004976.2
	KRAS	NM_033360.4	MANE Plus Clinical	c.*22C>G		3_prime_UTR	Exon 6 of 6	NP_203524.1	P01116-1
	KRAS	NM_001369787.1		c.468C>G	p.Phe156Leu	missense	Exon 5 of 5	NP_001356716.1	P01116-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.468C>G	p.Phe156Leu	missense	Exon 5 of 5	ENSP00000308495.3	P01116-2
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.*22C>G		3_prime_UTR	Exon 6 of 6	ENSP00000256078.5	P01116-1
	KRAS	ENST00000685328.1		c.468C>G	p.Phe156Leu	missense	Exon 5 of 5	ENSP00000508921.1	P01116-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiofaciocutaneous syndrome 2 (1)
1	-	-	KRAS-related disorder (1)
1	-	-	not provided (1)
1	-	-	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.46	D
PhyloP100		6.2
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.96	D
Vest4		0.88
MutPred		0.82		Gain of catalytic residue at V152 (P = 0.1003)
MVP		0.97
ClinPred		0.96	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=14/86	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: rs104894362; hg19: chr12-25362828; COSMIC: COSV55666258; COSMIC: COSV55666258;