rs727504662

Variant names:

• chr12-25227310-T-A
• rs727504662
• NM_033360.4:c.214A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-25227310-T-A
• chr12-25227310-T-G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS1 PM1 PM2 PP2 PP5_Very_Strong

The NM_033360.4(KRAS):​c.214A>T​(p.Met72Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M72I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_033360.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.00
• Publications: 9 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• Noonan syndrome

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

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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS1: Transcript NM_033360.4 (KRAS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_033360.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 65 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 2.3177 (below the threshold of 3.09). Trascript score misZ: 2.7433 (below the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 2, Noonan syndrome 3, Noonan syndrome, Costello syndrome, linear nevus sebaceous syndrome.
• PP5: Variant 12-25227310-T-A is Pathogenic according to our data. Variant chr12-25227310-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 179141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033360.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	NM_033360.4	MANE Plus Clinical	c.214A>T	p.Met72Leu	missense	Exon 3 of 6	NP_203524.1
	KRAS	NM_004985.5	MANE Select	c.214A>T	p.Met72Leu	missense	Exon 3 of 5	NP_004976.2
	KRAS	NM_001369786.1		c.214A>T	p.Met72Leu	missense	Exon 3 of 6	NP_001356715.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRAS	ENST00000256078.10	TSL:1 MANE Plus Clinical	c.214A>T	p.Met72Leu	missense	Exon 3 of 6	ENSP00000256078.5
	KRAS	ENST00000311936.8	TSL:1 MANE Select	c.214A>T	p.Met72Leu	missense	Exon 3 of 5	ENSP00000308495.3
	KRAS	ENST00000685328.1		c.214A>T	p.Met72Leu	missense	Exon 3 of 5	ENSP00000508921.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RASopathy Pathogenic:2

Feb 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KRAS c.214A>T (p.Met72Leu) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251324 control chromosomes (gnomAD). Another variant (c.214A>C) causing the same amino acid change (i.e. p.Met72Leu) has been reported in the literature, segregating with disease, in 3 affected individuals from one family affected with Noonan syndrome (Brasil_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for c.214A>T to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. One of the submitters cites evidence of the variant identified in 1 individual with clinical features of Noonan syndrome and segregated with disease in 1 affected relative (SCV000205637.4). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Based on the evidence outlined above, the variant was classified as pathogenic.

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 72 of the KRAS protein (p.Met72Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 22488932, 35979676; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179141). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.

Noonan syndrome Pathogenic:1

Nov 12, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Met72Leu variant in KRAS (c.214A>T) has been identified by our laboratory in 1 individual with clinical features of Noonan syndrome and segregated with di sease in 1 affected relative. Additionally, a different nucleotide change (c.214 A>C ) resulting in the same p.Met72Leu variant has also been reported in 1 indiv idual with clinical features of Noonan syndrome, who was de novo for the variant , and passed the variant on to 2 relatives with clinical features of Noonan sy ndrome (Brasil 2012). Both variants were absent from large population studies. I n summary, this variant meets our criteria to be classified as pathogenic for No onan syndrome in an autosomal dominant manner based upon de novo occurrence, seg regation studies, and absence from controls.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	0.97
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.85	L
PhyloP100		8.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.028	D
Sift4G	Benign	0.088	T
Polyphen		0.13	B
Vest4		0.71
MutPred		0.67		Gain of catalytic residue at T74 (P = 0.0197)
MVP		0.87
MPC		1.6
ClinPred		0.83	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.86
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs727504662; hg19: chr12-25380244;