12-25227330-C-A

Variant names:

• chr12-25227330-C-A
• rs1555194026
• NM_004985.5:c.194G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PS4_Supporting PS2

This summary comes from the ClinGen Evidence Repository: The c.194G>T (p.Ser65Ile) variant in KRAS was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 2 probands with clinical features of a RASopathy (PS4_Supporting; SCV000599968.1, PMID:26822237, 25326635, Invitae internal data). The variant arose de novo in one of the probands with confirmed parentage (PS2; SCV000599968.1, PMID:26822237, 25326635). The variant is located in KRAS, 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). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581):, PS2, PS4_Supporting, PM2, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA384152083/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.194G>T	p.Ser65Ile	missense_variant	Exon 3 of 5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.194G>T	p.Ser65Ile	missense_variant	Exon 3 of 5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

RASopathy Pathogenic:2 Uncertain:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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: 438796). This missense change has been observed in individual(s) with clinical features of KRAS-related conditions (PMID: 25326635, 26822237). 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 serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 65 of the KRAS protein (p.Ser65Ile). -

May 18, 2020

ClinGen RASopathy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.194G>T (p.Ser65Ile) variant in KRAS was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 2 probands with clinical features of a RASopathy (PS4_Supporting; SCV000599968.1, PMID: 26822237, 25326635, Invitae internal data). The variant arose de novo in one of the probands with confirmed parentage (PS2; SCV000599968.1, PMID:26822237, 25326635). The variant is located in KRAS, 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). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581):, PS2, PS4_Supporting, PM2, PP2. -

Sep 01, 2017

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Likely pathogenicity based on finding it once in our laboratory de novo in an 8-year-old female with global delays, hypotonia, failure to thrive, short stature, thin corpus callosum, epilepsy, small optic nerve, ptosis, coarse facies, joint contractures, hypothyroidism -

Noonan syndrome 3 Pathogenic:1

Aug 25, 2014

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Likely pathogenicity based on finding it once in this study de novo in a 8-year-old female with plexiform neurofibroma, hypertelorism, ptosis, pulmonic stenosis, scoliosis, skeletal anomalies, developmental delay -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.2	L;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.56		Loss of disorder (P = 0.0015);Loss of disorder (P = 0.0015);
MVP		0.98
MPC		2.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.87

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: rs1555194026; hg19: chr12-25380264; COSMIC: COSV55620918; COSMIC: COSV55620918;