rs104894360

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4PM2_SupportingPS3_ModeratePP3PP2PS2

This summary comes from the ClinGen Evidence Repository: The c.458A>T variant in the KRAS gene is a missense variant predicted to cause substitution of asparagine by valine at amino acid 153 (p.Asp153Val). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.791 supporting a deleterious impact to KRAS function (PP3). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). This variant has been reported in at least 6 individuals with four confirmed de novo occurrences with clinical features of a RASopathy (PS4, PS2_VeryStrong; PMIDs: 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). In vitro functional studies showed that this variant enhanced RAS/MEK/ERK activation (PS3_Moderate; PMID:17875937, 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA256478/MONDO:0021060/044

Frequency

Genomes: not found (cov: 33)

Consequence

KRAS
NM_004985.5 missense

Scores

8
5
2

Clinical Significance

Pathogenic reviewed by expert panel P:17

Conservation

PhyloP100: 7.63
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PS2
For more information check the summary or visit ClinGen Evidence Repository.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM2
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
KRASNM_004985.5 linkc.458A>T p.Asp153Val missense_variant Exon 5 of 5 ENST00000311936.8 NP_004976.2 P01116-2A0A024RAV5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRASENST00000311936.8 linkc.458A>T p.Asp153Val missense_variant Exon 5 of 5 1 NM_004985.5 ENSP00000308495.3 P01116-2

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
LINK: link

Submissions by phenotype

Noonan syndrome 3 Pathogenic:6
Nov 18, 2018
Baylor Genetics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 24, 2021
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Mar 12, 2013
UCLA Clinical Genomics Center, UCLA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 01, 2006
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Oct 09, 2023
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PS3,PS2_STR,PS4_SUP,PP3 -

Aug 30, 2023
Genomic Medicine Lab, University of California San Francisco
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:3
Jun 13, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Aug 31, 2018
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 26, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

RASopathy Pathogenic:2
Dec 03, 2024
ClinGen RASopathy Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The c.458A>T variant in the KRAS gene is a missense variant predicted to cause substitution of asparagine by valine at amino acid 153 (p.Asp153Val). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.791 supporting a deleterious impact to KRAS function (PP3). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). This variant has been reported in at least 6 individuals with four confirmed de novo occurrences with clinical features of a RASopathy (PS4, PS2_VeryStrong; PMIDs: 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). In vitro functional studies showed that this variant enhanced RAS/MEK/ERK activation (PS3_Moderate; PMID: 17875937, 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024) -

Nov 14, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 12587). 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: 16474404, 20949621). For these reasons, this variant has been classified as Pathogenic. -

not specified Pathogenic:1
Apr 20, 2017
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1
May 12, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Mar 01, 2006
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Noonan syndrome 1 Pathogenic:1
-
Molecular Genetics, Centre for Human Genetics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1
Sep 08, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

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
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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