rs1555194026

Variant names:

• chr12-25227330-C-A
• rs1555194026
• NM_033360.4:c.194G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-25227330-C-A
• chr12-25227330-C-G
• chr12-25227330-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP2 PM2 PS2 PS4_Supporting

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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• cardiofaciocutaneous syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
• linear nevus sebaceous syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004985.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	NM_033360.4	MANE Plus Clinical	c.194G>T	p.Ser65Ile	missense	Exon 3 of 6	NP_203524.1	P01116-1
	KRAS	NM_004985.5	MANE Select	c.194G>T	p.Ser65Ile	missense	Exon 3 of 5	NP_004976.2
	KRAS	NM_001369786.1		c.194G>T	p.Ser65Ile	missense	Exon 3 of 6	NP_001356715.1	P01116-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.194G>T	p.Ser65Ile	missense	Exon 3 of 6	ENSP00000256078.5	P01116-1
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.194G>T	p.Ser65Ile	missense	Exon 3 of 5	ENSP00000308495.3	P01116-2
	KRAS	ENST00000692768.1		c.-5G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000510254.1	A0A8I5KUB5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	RASopathy (3)
1	-	-	Noonan syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.2	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.56		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

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