rs121913529

chr12-25245350-C-Achr12-25245350-C-Gchr12-25245350-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_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. G12D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 7.89

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 16 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 in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-25245350-C-T is described in ClinVar as [Likely_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
KRAS	NM_033360.4	c.35G>T	p.Gly12Val	missense_variant	2/6	ENST00000256078.10
KRAS	NM_004985.5	c.35G>T	p.Gly12Val	missense_variant	2/5	ENST00000311936.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10	c.35G>T	p.Gly12Val	missense_variant	2/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.35G>T	p.Gly12Val	missense_variant	2/5	1	NM_004985.5	P4

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

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:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
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, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	- -

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

-

- -

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

- -

Neoplasm of ovary Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

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’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 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

Invitae

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. -

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
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

Other links and lift over

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