12-25227346-C-T

Position:

• chr12-25227346-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004985.5(KRAS):​c.178G>A​(p.Gly60Ser) 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. 12/21 in silico tools predict a damaging 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. G60R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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 18 ACMG points.

• PM1: In a helix (size 2) in uniprot entity RASK_HUMAN there are 4 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 chr12-25227346-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 12-25227346-C-T is Pathogenic according to our data. Variant chr12-25227346-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12597.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_033360.4	c.178G>A	p.Gly60Ser	missense_variant	3/6	ENST00000256078.10	NP_203524.1
KRAS	NM_004985.5	c.178G>A	p.Gly60Ser	missense_variant	3/5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000256078.10	c.178G>A	p.Gly60Ser	missense_variant	3/6	1	NM_033360.4	ENSP00000256078	A1
KRAS	ENST00000311936.8	c.178G>A	p.Gly60Ser	missense_variant	3/5	1	NM_004985.5	ENSP00000308495	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 3 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Prenatal Genetic Diagnosis Laboratory, The Chinese University of Hong Kong	Jul 05, 2021	This variant c.178G>A(p.G60S) was previously reported to be de novo in a patient with Noonan syndrome [PMID:19396835] (PS2). The p.Gly60 amino acid residue in KRAS has been determined to be clinically significant and confirmed by functional studies [PMID: 16474404, 20949621, 26242988, 28650561] (PM1). The variant is absent in the gnomAD database (PM2). Computational evidence support a deleterious effect on the gene product (PP3) .This variant has been classified as pathogenic by multiple labs in ClinVar [Variation ID: 12597] (PP5). This variant c.178G>A(p.G60S) is interpreted as pathogenic according to ACMG/AMP guidelines. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Mar 25, 2022	The c.178G>A;p.(Gly60Ser) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12597; PMID: 19396835) -PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (RAS) - PM1. This variant is not present in population databases (rs104894359- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 12586) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 19396835) - PM6. Missense variant in KRAS that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic -

Cardiofaciocutaneous syndrome 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Aug 28, 2019

A heterozygous missense variant, NM_004985.4(KRAS):c.178G>A, has been identified in exon 3 of 5 of the KRAS gene. The variant is predicted to result in a minor amino acid change from glycine to serine at position 60 of the protein (NP_004976.2(KRAS):p.(Gly60Ser)). The glycine residue at this position has very high conservation (100 vertebrates, UCSC) and is known as a mutational hotspot for Noonan syndrom and related disorders that locates within the critical binding and interaction site of Ras domain (Gremer, L. et al. (2011)). In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD). The variant has been previously described as a known pathogenic variant in multiple patients with Noonan syndrome (ClinVar, Kratz, CP. et al. (2009), Leung, GKC. et al. (2018), Chen, H. et al. (2019)). Multiple variants in the same codon resulting in various changes have also been reported as pathogenic (ClinVar, Zenker, M. et al. (2007), Nosan, G. et al. (2013), Chen, H. et al. (2019)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 25, 2022

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 28639239, 19396835, 30732632, 31219622, 35441720) -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly60 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16474404, 26242988, 28650561). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 12597). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19396835, 30732632). 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 glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 60 of the KRAS protein (p.Gly60Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.78		Gain of catalytic residue at L56 (P = 0.0034);Gain of catalytic residue at L56 (P = 0.0034);
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.95

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: rs104894359; hg19: chr12-25380280; COSMIC: COSV55849913; COSMIC: COSV55849913;