rs397517042

Positions:

• chr12-25209896-A-C
• chr12-25209896-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_004985.5(KRAS):​c.466T>G​(p.Phe156Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 9/15 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.89

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]

KRAS (HGNC:):

ACMG classification

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, 0.935
• PP5: Variant 12-25209896-A-C is Pathogenic according to our data. Variant chr12-25209896-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRAS	NM_004985.5	c.466T>G	p.Phe156Val	missense_variant	5/5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.466T>G	p.Phe156Val	missense_variant	5/5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2018

The F156V variant in the KRAS gene has been reported previously in an individual with Noonan syndrome (Al Hawas, 2012). The F156V variant is not observed in large population cohorts (Lek et al., 2016). The F156V variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Two pathogenic missense variants at this same residue (F156L, F156I) have been reported in association with disorders of the Noonan spectrum (Zenker et al., 2007), supporting the functional importance of this region of the protein. We interpret F156V as a pathogenic variant. -

Noonan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 08, 2014

The Phe156Val variant in KRAS has now been identified in three individuals in on e family with clinical features of a Noonan spectrum disorder (LMM unpublished d ata). This variant is absent from large population studies. In addition, two dif ferent amino acid changes at the same codon, Phe156Leu and Phe156Ile, have been reported to occur de novo in three individuals with a Noonan spectrum disorder ( Zenker 2007, Sovik 2007). Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to determi ne pathogenicity. In summary, this variant is likely pathogenic, though addition al studies are required to fully establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.58	D
PROVEAN	Pathogenic	-6.2	D;N
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;T
Sift4G	Pathogenic	0.0	D;T
Polyphen		1.0	D;.
Vest4		0.89
MutPred		0.81		Gain of MoRF binding (P = 0.0822);.;
MVP		0.99
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517042; hg19: chr12-25362830;