rs104894361

Positions:

• chr12-25245370-T-A
• chr12-25245370-T-C
• chr12-25245370-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4_Moderate PM2 PM6_Strong PP2 PP3

This summary comes from the ClinGen Evidence Repository: The c.15A>T (p.Lys5Asn) variant in KRAS has been reported in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID:17056636, GeneDx internal data). This variant was absent from large population studies (PM2; gnomad.broadinstitute.org). The p.Lys5Asn variant has been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; PMID:17056636, GeneDx, EGL Genetics internal data, ClinVar SCV000202928.7). Computational prediction tools and conservation analysis suggest that the p.Lys5Asn variant may impact protein function (PP3). 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). 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): PS4_Moderate, PM6_Strong, PM2, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA234191/MONDO:0018997/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 0.726

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 10 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRAS	NM_004985.5	c.15A>T	p.Lys5Asn	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.15A>T	p.Lys5Asn	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

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2017

- -

Cardiofaciocutaneous syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2008

- -

Noonan syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Apr 03, 2017

The c.15A>T (p.Lys5Asn) variant in KRAS has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data GTR ID: 26957, 506381 PMID 17056636). The variant has been detected in This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The p.Lys5Asn variant has been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; EGL genetics internal data GTR ID: 500060; PMID: 17056636; ClinVar SCV000202928.6). Computational prediction tools and conservation analysis suggest that the p.Lys5Asn variant may impact the protein (PP3). 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). 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, PM2, PS4_Moderate, PP3, PP2) -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 22, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;.;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	2.9	M;.;M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.97
MutPred		0.75		Gain of catalytic residue at E3 (P = 8e-04);Gain of catalytic residue at E3 (P = 8e-04);Gain of catalytic residue at E3 (P = 8e-04);Gain of catalytic residue at E3 (P = 8e-04);
MVP		0.99
MPC		2.9
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs104894361; hg19: chr12-25398304; COSMIC: COSV56100680;