12-25245350-C-A

Position:

chr12-25245350-C-A

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

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]

KRAS links:

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
KRAS	NM_033360.4 linkuse as main transcript	c.35G>T	p.Gly12Val	missense_variant	2/6	ENST00000256078.10	NP_203524.1
KRAS	NM_004985.5 linkuse as main transcript	c.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
KRAS	ENST00000256078.10 linkuse as main transcript	c.35G>T	p.Gly12Val	missense_variant	2/6	1	NM_033360.4	ENSP00000256078	A1	P01116-1
KRAS	ENST00000311936.8 linkuse as main transcript	c.35G>T	p.Gly12Val	missense_variant	2/5	1	NM_004985.5	ENSP00000308495	P4	P01116-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460566

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

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.:

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 submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2020	Observed 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 provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

Nevus sebaceous

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Oct 25, 2012	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 10, 2012	- -

Cerebral arteriovenous malformation

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 06, 2018	- -
Pathogenic, no assertion criteria provided	research	Arin Greene Laboratory, Boston Children's Hospital, Harvard Medical School	-	- -

Non-small cell lung carcinoma

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 15, 2018	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	Mar 10, 2016	- -

Carcinoma of pancreas

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 10, 2012

- -

Lung sarcomatoid carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Salgia Laboratory, City of Hope

- -

Ovarian neoplasm

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Acute myeloid leukemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Chronic myelogenous leukemia, BCR-ABL1 positive

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Druker Lab, Oregon Health and Sciences University

Oct 10, 2022

- -

Linear nevus sebaceous syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Sep 22, 2023

The 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‚Äôs 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 submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 15, 2018

proposed classification - variant undergoing re-assessment, contact laboratory -

Neoplasm of the large intestine

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Thyroid tumor

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

RASopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This 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 submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;.;D;.

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;T;T;T

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

1.8

L;.;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.90

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over