rs121913535

Positions:

• chr12-25245348-C-A
• chr12-25245348-C-G
• chr12-25245348-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.37G>T​(p.Gly13Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G13D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• 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 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 chr12-25245347-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 12-25245348-C-A is Pathogenic according to our data. Variant chr12-25245348-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-25245348-C-A is described in Lovd as [Pathogenic]. Variant chr12-25245348-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRAS	NM_004985.5	c.37G>T	p.Gly13Cys	missense_variant	2/5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.37G>T	p.Gly13Cys	missense_variant	2/5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 4 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 10, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Diagnostic Genetics, Severance Hospital, Yonsei University College of Medicine	Jan 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 29493581. Predicted Consequence/Location:). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000045123 / PMID: 27577878). Different missense changes at the same codon (p.Gly13Ala, p.Gly13Arg, p.Gly13Asp, p.Gly13Ser, p.Gly13Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012580, VCV000012593, VCV000045124, VCV000375967, VCV000375968, VCV001691382 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 22, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2022	Published functional studies demonstrate that this variant causes increased RAS activation (Niemela et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 19661383, 22306671, 17517660, 25705018, 25691160, 21063026, 34056834, 22571758, 29493581, 21079152, 17875937, 27577878, 35116442) -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

KRAS-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant has been previously reported as a somatic/ mosaic change in patients with RAS-associated autoimmune leukoproliferative disorder (PMID: 27577878, 21079152). Cells transfected with a plasmid-encoding mutant G13C showed an increased amount of active RAS versus wild-type KRAS suggesting a gain-of-function effect (PMID: 21079152). The c.37G>T (p.Gly13Cys) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.37G>T (p.Gly13Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.37G>T (p.Gly13Cys) variant is classified as Pathogenic. -

Non-small cell lung carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 17, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.3	M;.;M;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.6	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.94
MutPred		0.74		Gain of catalytic residue at S17 (P = 0);Gain of catalytic residue at S17 (P = 0);Gain of catalytic residue at S17 (P = 0);Gain of catalytic residue at S17 (P = 0);
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913535; hg19: chr12-25398282; COSMIC: COSV55497378;