chr12-25245350-C-G

Position:

chr12-25245350-C-G

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>C(p.Gly12Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 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 Likely 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: 0.0000014 ( 0 hom. )

Consequence

KRAS
NM_004985.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O: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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a binding_site (size 8) in uniprot entity RASK_HUMAN there are 13 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, 0.874

PP5

Variant 12-25245350-C-G is Pathogenic according to our data. Variant chr12-25245350-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRAS	NM_004985.5 link	c.35G>C	p.Gly12Ala	missense_variant	2/5	ENST00000311936.8	NP_004976.2	P01116-2A0A024RAV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8 link	c.35G>C	p.Gly12Ala	missense_variant	2/5	1	NM_004985.5	ENSP00000308495.3		P01116-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple myeloma

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center

Aug 31, 2019

- -

Malignant tumor of urinary bladder;C0023467:Acute myeloid leukemia;C0024623:Gastric cancer;C0242379:Lung cancer;C0346153:Familial cancer of breast;C0917804:Cerebral arteriovenous malformation;C1838329:Toriello-Lacassie-Droste syndrome;C1860991:Noonan syndrome 3;C2674723:Autoimmune lymphoproliferative syndrome type 4;C2931038:Familial pancreatic carcinoma;C3809005:Cardiofaciocutaneous syndrome 2;C4552097:Linear nevus sebaceous syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PM5_Strong+PP3_Moderate+PS4 -

KRAS-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2022

The KRAS c.35G>C variant is predicted to result in the amino acid substitution p.Gly12Ala. To our knowledge, this variant has not been reported as a germline variant in individuals with Noonan/RASopathy phenotypes. However, several KRAS missense variants affecting Gly12, including p.Gly12Ala, have been reported as a somatic variant in multiple cancers (see for example - Brose et al. 2002. PubMed ID: 12460918; Lièvre et al. 2006. PubMed ID: 16618717). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

- -

Non-small cell lung carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 07, 2007

- -

Lung cancer

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University

- -

Gallbladder cancer

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Institute of Medical Sciences, Banaras Hindu University

Oct 30, 2020

- -

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

0.96

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

.;.;D;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.091

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Benign

1.2

L;.;L;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.5

D;D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D

Polyphen

0.90

P;.;P;.

Vest4

0.83

MutPred

0.75

Gain of catalytic residue at G12 (P = 0);Gain of catalytic residue at G12 (P = 0);Gain of catalytic residue at G12 (P = 0);Gain of catalytic residue at G12 (P = 0);

MVP

0.97

MPC

2.5

ClinPred

0.98

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.91

gMVP

0.97

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