rs104894364

chr12-25227351-G-Achr12-25227351-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_004985.5(KRAS):c.173C>T(p.Thr58Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,754 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 (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.98

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 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 12-25227351-G-A is Pathogenic according to our data. Variant chr12-25227351-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12588.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_033360.4	c.173C>T	p.Thr58Ile	missense_variant	3/6	ENST00000256078.10
KRAS	NM_004985.5	c.173C>T	p.Thr58Ile	missense_variant	3/5	ENST00000311936.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10	c.173C>T	p.Thr58Ile	missense_variant	3/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.173C>T	p.Thr58Ile	missense_variant	3/5	1	NM_004985.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 3 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	Feb 28, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Apr 14, 2022	ACMG categories: PS3,PM1,PM2,PM6,PP3,PP5 -

Noonan syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The c.173C>T (p.Thr58Ile) variant in KRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6_Strong; PMID 23321623, 20112233, 16921267, 16474405, 22488832, 18247425, 20949621). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Thr58Ile variant may impact protein function (PS3; PMID: 23321623, 20949621, 16921267). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of KRAS (PM1; PMID 29493581). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr58Ile variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS3, PM2, PM1, PP2, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 25, 2014	The Thr58Ile variant in KRAS has been previously reported in at least one fetus, one infant, and one child with clinical features of Noonan syndrome (Schubbert 2006, Houweling 2010, Croonen 2013, LMM-unpublished data). In both the fetus and the infant, the variant was reported to be de novo (Schubbert 2006, Croonen 201 3). Functional studies show that this variant impacts the protein's GTPase activ ity and leads to overall enhanced downstream signaling (Schubbert 2006, Gremer 2 010). In addition, this variant was absent from large population studies. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp gm.partners.org/LMM). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2017

Heterozygous for the T58I mutation in the KRAS gene, consistent with the diagnosis of a disorder in the Noonan syndrome spectrum.Heterozygous for the T58I mutation in the KRAS gene, consistent with the diagnosis of a disorder in the Noonan syndrome spectrum.p.Thr58Ile (ACA>ATA): c.173 C>T in exon 3 of the KRAS gene (NM_004985.3)The T58I missense mutation in the KRAS gene has been reported previously in association with Noonan Syndrome (Schubbert et al., 2006), and a mutation in a neighboring residue, G60R, has been reported in associated with Cardio-Facio-Cutaneous (CFC) syndrome (Niihori et al., 2006). Therefore, the identification of the T58I mutation is consistent with a diagnosis of an autosomal dominant disorder of the Noonan-CFC-Costello syndrome spectrum. The variant is found in NOONAN panel(s). -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 04, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KRAS function (PMID: 16474405, 20949621). 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. ClinVar contains an entry for this variant (Variation ID: 12588). This missense change has been observed in individual(s) with Noonan syndrome and Costello syndrome and Noonan syndrome (PMID: 16474405, 17704260, 19396835, 20186801). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 58 of the KRAS protein (p.Thr58Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.8	M;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.83		Gain of catalytic residue at A59 (P = 0);Gain of catalytic residue at A59 (P = 0);
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs104894364; hg19: chr12-25380285; COSMIC: COSV55527371; COSMIC: COSV55527371;