rs121913529

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_004985.5(KRAS):​c.35G>T​(p.Gly12Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,566 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G12C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KRAS
NM_004985.5 missense

Scores

12
5
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19O:1

Conservation

PhyloP100: 7.89
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-25245351-C-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.924
PP5
Variant 12-25245350-C-A is Pathogenic according to our data. Variant chr12-25245350-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-25245350-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KRASNM_033360.4 linkuse as main transcriptc.35G>T p.Gly12Val missense_variant 2/6 ENST00000256078.10 NP_203524.1
KRASNM_004985.5 linkuse as main transcriptc.35G>T p.Gly12Val missense_variant 2/5 ENST00000311936.8 NP_004976.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KRASENST00000256078.10 linkuse as main transcriptc.35G>T p.Gly12Val missense_variant 2/61 NM_033360.4 ENSP00000256078 A1P01116-1
KRASENST00000311936.8 linkuse as main transcriptc.35G>T p.Gly12Val missense_variant 2/51 NM_004985.5 ENSP00000308495 P4P01116-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460566
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726502
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:19Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 25, 2020Observed as a somatic variant in intracranial AVM specimens and sebaceous nevi (Goss et al., 2019; Groesser et al., 2012; Levinsohn et al., 2013); Observed as a presumably somatic variant associated with malignancies including non-small cell lung cancer, pancreatic carcinoma, and ovarian carcinoma (Doebele et al., 2012; Motojima et al., 1993); Auner et al., 2009); Published functional studies demonstrated that G12V impaired function and enhanced downstream signaling (Gremer et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 15696205, 22669205, 21169357, 17384584, 2278970, 21975775, 25157968, 24803665, 23096712, 19047918, 19018267, 18316791, 17704260, 16618717, 19679400, 19075190, 29298116, 22897852, 22407852, 21398618, 21228335, 20609353, 19881948, 20949621, 31891627, 26372703, 22683711, 22235099, 8439212, 19358724) -
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-- -
Nevus sebaceous Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyYale Center for Mendelian Genomics, Yale UniversityOct 25, 2012- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 10, 2012- -
Cerebral arteriovenous malformation Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 06, 2018- -
Pathogenic, no assertion criteria providedresearchArin Greene Laboratory, Boston Children's Hospital, Harvard Medical School-- -
Non-small cell lung carcinoma Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 15, 2018proposed classification - variant undergoing re-assessment, contact laboratory -
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Mar 10, 2016- -
Carcinoma of pancreas Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 10, 2012- -
Lung sarcomatoid carcinoma Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingSalgia Laboratory, City of Hope-- -
Ovarian neoplasm Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Oct 02, 2014- -
Acute myeloid leukemia Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Oct 02, 2014- -
Chronic myelogenous leukemia, BCR-ABL1 positive Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDruker Lab, Oregon Health and Sciences UniversityOct 10, 2022- -
Linear nevus sebaceous syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingClinical Genomics Laboratory, Washington University in St. LouisSep 22, 2023The KRAS c.35G>T (p.Gly12Val) variant was identified at an allelic fraction consistent with somatic origin. It has been identified in individuals with Schimmelpenning-Feuerstein-Mims syndrome and arteriovenous malformation caused by somatic pathogenic variants (Groesser L et al., PMID: 22683711; Serio VB et al., PMID: 35807022; Palmieri M et al., PMID: 34617046; Ten Broek RW et al., PMID: 30677207; Al-Olabi L et al., PMID: 29461977). This variant has been reported in the ClinVar database as pathogenic by eight submitters (ClinVar ID: 12583) in both a germline and a somatic state. It also has been reported in 11,239 cases in the cancer database (COSMIC ID: COSV55497419). KRAS c.35G>T (p.Gly12Val) is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the switch I region, amino acids 32-40, of KRAS that is defined as a critical functional domain (Pacold ME et al., PMID: 11136978). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KRAS function. The KRAS gene is defined by ClinGen’s RASopathy Expert Panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Gelb BD et al., PMID: 2949358). Functional studies using animals show that this variant induces vascular malformation phenotypes similar to observed in humans (Fish JE et al., PMID: 32552404). Other variants in the same codon, c.35G>A (p.Gly12Asp) have been reported in individuals with Schimmelpenning-Feuerstein-Mims syndrome and nevus sebaceous and are considered pathogenic (Mitchell BJ et al., PMID: 30394973; Levinsohn JL et al., PMID: 23096712; ClinVar ID: 12582). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, KRAS c.35G>T (p.Gly12Val) variant is classified as pathogenic. -
Juvenile myelomonocytic leukemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 15, 2018proposed classification - variant undergoing re-assessment, contact laboratory -
Neoplasm of the large intestine Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Jul 14, 2015- -
Thyroid tumor Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Oct 02, 2014- -
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 13, 2023This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the KRAS protein (p.Gly12Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 12583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function. Experimental studies have shown that this missense change affects KRAS function (PMID: 20949621, 21044336). This variant disrupts the p.Gly12 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17704260, 26242988). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Neoplasm Other:1
-, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalJul 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
.;.;D;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.87
D;T;T;T
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.92
D;D;D;D
MetaSVM
Uncertain
0.54
D
MutationAssessor
Benign
1.8
L;.;L;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-7.0
D;D;D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0070
D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0
D;.;D;.
Vest4
0.92
MutPred
0.77
Gain of catalytic residue at V14 (P = 0);Gain of catalytic residue at V14 (P = 0);Gain of catalytic residue at V14 (P = 0);Gain of catalytic residue at V14 (P = 0);
MVP
0.99
MPC
2.4
ClinPred
0.99
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.97
gMVP
0.98

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: rs121913529; hg19: chr12-25398284; COSMIC: COSV55497419; API