rs104894360

Positions:

• chr12-25209904-T-A
• chr12-25209904-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP2 PP3 PM6_Strong PM5 PS3

This summary comes from the ClinGen Evidence Repository: The c.458A>T (p.Asp153Val) variant in KRAS has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). In vitro functional studies provide some evidence that the p.Asp153Val variant may impact protein function (PS3; PMID 20949621). The p.Asp153Val variant in KRAS has been reported in the literature in at least 4 patients with clinical features of a RASopathy (PS4_Moderate; LMM internal data GTR Lab ID: 21766, ClinVar SCV000203924.4; PMID 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PS4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA256478/MONDO:0018997/004

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: 7.63

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_004985.5	c.458A>T	p.Asp153Val	missense_variant	5/5	ENST00000311936.8
KRAS	NM_033360.4	c.*12A>T		3_prime_UTR_variant	6/6	ENST00000256078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000311936.8	c.458A>T	p.Asp153Val	missense_variant	5/5	1	NM_004985.5	P4
KRAS	ENST00000256078.10	c.*12A>T		3_prime_UTR_variant	6/6	1	NM_033360.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 3 Pathogenic:6

Pathogenic, no assertion criteria provided	research	Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	Dec 24, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Nov 18, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 09, 2023	Criteria applied: PS3,PS2_STR,PS4_SUP,PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Mar 12, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Aug 30, 2023	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2023	Published functional studies have demonstrated that D153V increases the activity of the KRAS protein compared to wild type (Mazhab-Jafari et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); 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: 20648242, 17551339, 17056636, 20949621, 24703799, 21871821, 16474405, 16474404, 16987887, 16773572, 17875937, 24803665, 21062266, 29025208, 30732632, 30138938, 30692697, 31219622, 31292302, 36028527, 18456719, 34358384, 25941399) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 26, 2021	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 20, 2017

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 12, 2014

The Asp153Val variant has been associated with the clinical features of Noonan s yndrome and Cardio-facio-cutaneous syndrome (CFC; Nystrom 2008, Schubbert 2007, Tang 2007, Zenker 2007, Carta 2006, Niihori 2006, Schubbert 2006). In several of these individuals the variant was shown to have occurred de novo. In summary, t his variant meets our criteria to be classified as pathogenic (http://pcpgm.part ners.org/LMM). -

Cardiofaciocutaneous syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2006

- -

Noonan syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics, Centre for Human Genetics

-

- -

Malignant tumor of urinary bladder;C0023467:Acute myeloid leukemia;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0684249:Lung carcinoma;C0917804:Cerebral arteriovenous malformation;C1708349:Hereditary diffuse gastric adenocarcinoma;C1860991:Noonan syndrome 3;C2674723:Autoimmune lymphoproliferative syndrome type 4;C3809005:Cardiofaciocutaneous syndrome 2;C4552097:Linear nevus sebaceous syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Noonan syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Nov 15, 2018

The c.458A>T (p.Asp153Val) variant in KRAS has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). In vitro functional studies provide some evidence that the p.Asp153Val variant may impact protein function (PS3; PMID 20949621). The p.Asp153Val variant in KRAS has been reported in the literature in at least 4 patients with clinical features of a RASopathy (PS4_Moderate; LMM internal data GTR Lab ID: 21766, ClinVar SCV000203924.4; PMID 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PS4_Moderate. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2022

The c.458A>T (p.D153V) alteration is located in exon 5 (coding exon 4) of the KRAS gene. This alteration results from an A to T substitution at nucleotide position 458, causing the aspartic acid (D) at amino acid position 153 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple unrelated individuals with features of Noonan syndrome and/or cardiofaciocutaneous syndrome. This variant occurred de novo in the majority of these individuals (Carta, 2006; Niihori, 2006; Schubbert, 2006; Zenker, 2007). This amino acid position is highly conserved in available vertebrate species. In vitro functional studies suggest that p.D153V increases activation of MAPK signaling pathway (Niihori, 2006; Gremer, 2011). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 01, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KRAS function (PMID: 16474404, 20949621). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 12587). This missense change has been observed in individual(s) with Noonan syndrome or cardiofaciocutaneous syndrome (PMID: 16474405, 16773572, 17056636, 18456719, 21062266, 21871821, 24703799). 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 aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 153 of the KRAS protein (p.Asp153Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.20	D
MutationTaster	Benign	1.0	A;A;A
PROVEAN	Pathogenic	-5.0	D;N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.91	P;.
Vest4		0.87
MutPred		0.75		Gain of MoRF binding (P = 0.036);.;
MVP		0.93
ClinPred		0.96	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs104894360; hg19: chr12-25362838; COSMIC: COSV55596451; COSMIC: COSV55596451;