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rs121913529

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2_SupportingPM5PP3_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 was absent in control chromosomes in GnomAD Genomes 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. G12C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KRAS
NM_004985.5 missense

Scores

11
5
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 7.89

Links

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1
?
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_004985.5
PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 32.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr12-25245350-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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 UniProt
KRASNM_033360.4 linkuse as main transcriptc.35G>T p.Gly12Val missense_variant 2/6 ENST00000256078.10
KRASNM_004985.5 linkuse as main transcriptc.35G>T p.Gly12Val missense_variant 2/5 ENST00000311936.8

Ensembl

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

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460566
Hom.:
0
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

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
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, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2022- -
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 providedresearchArin Greene Laboratory, Boston Children's Hospital, Harvard Medical School-- -
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 06, 2018- -
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-- -
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- -
Neoplasm of ovary Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Oct 02, 2014- -
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- -

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
26
Dann
Uncertain
1.0
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