rs104894362

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. 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 (★★). 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 19 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 2, Noonan syndrome 3, Noonan syndrome, Costello syndrome, linear nevus sebaceous syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.468C>G	p.Phe156Leu	missense_variant	Exon 5 of 5	ENST00000311936.8	NP_004976.2
KRAS	NM_033360.4	c.*22C>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000256078.10	NP_203524.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.468C>G	p.Phe156Leu	missense_variant	Exon 5 of 5	1	NM_004985.5	ENSP00000308495.3
KRAS	ENST00000256078.10	c.*22C>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_033360.4	ENSP00000256078.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiofaciocutaneous syndrome 2 Pathogenic:1

May 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

KRAS-related disorder Pathogenic:1

Mar 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KRAS c.468C>G variant is predicted to result in the amino acid substitution p.Phe156Leu. This variant has been reported in patients diagnosed with Costello syndrome (Patient 12 in Zenker et al. 2007. PubMed ID: 17056636), Noonan syndrome (Patient 24 in Table S4 in Bessis et al. 2019. PubMed ID: 30417923; Supplementary Table 1 in Li et al. 2019. PubMed ID: 31219622) and as de novo in a patient with cardio-facio-cutaneous (Søvik et al. 2009. PubMed ID: 21686750). 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 ). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In addition another variant impacting the same amino acid residue (p.Phe156Ile) has been documented in a patient with a KRAS-related disorder (Patient 11 in Zenker et al. 2007. PubMed ID: 17056636). Based on this evidence, the c.468C>G (p.Phe156Leu) variant is interpreted as pathogenic. -

not provided Pathogenic:1

May 19, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Heterozygous for the F156L mutation in the KRAS gene, consistent with the diagnosis of a disorder in the Noonan syndrome spectrum.p.Phe156Leu (TTC>TTG):c.468 C>G in exon 5 of the KRAS gene (NM_004985.3)The F156L missense mutation in the KRAS gene has been reported previously in a 14 month old male who was diagnosed with Costello syndrome with hypertrophic cardiomyopathy, ASD and pulmonic stenosis, developmental delay, and mild-moderate mental retardation, failure to thrive, severe feeding difficulties, loose and redundant skin with deep palmar and plantar creases, Dandy-Walker malformation, and facial dysmorphism (Zenker et al., 2007). Another missense mutation of the same codon, F156I, was described in a patient with features of both Noonan and CFC syndrome (Zenker et al., 2007). Additionally, functional in vitro studies have demonstrated that the F156L mutation results in profound activation of the MAPK pathway (Gremer et al, 2011). The variant is found in NOONAN panel(s). -

RASopathy Pathogenic:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.46	D
PhyloP100		6.2
PROVEAN	Pathogenic	-5.3	D;N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;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;