12-25227310-T-A

Position:

• chr12-25227310-T-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM1 PM2 PP5_Very_Strong

The NM_004985.5(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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.00

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PS1: Transcript NM_004985.5 (KRAS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a chain GTPase KRas, N-terminally processed (size 184) in uniprot entity RASK_HUMAN there are 29 pathogenic changes around while only 0 benign (100%) in NM_004985.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-25227310-T-A is Pathogenic according to our data. Variant chr12-25227310-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-25227310-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRAS	NM_004985.5	c.214A>T	p.Met72Leu	missense_variant	3/5	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.214A>T	p.Met72Leu	missense_variant	3/5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RASopathy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2020	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). A different variant (c.214A>C) giving rise to the same protein effect has been determined to be pathogenic (PMID: 22488932). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 179141). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with leucine at codon 72 of the KRAS protein (p.Met72Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2023	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. -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 12, 2015

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 v4.3

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;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.85	L;L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.5	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.028	D;D
Sift4G	Benign	0.088	T;T
Polyphen		0.13	B;B
Vest4		0.71
MutPred		0.67		Gain of catalytic residue at T74 (P = 0.0197);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504662; hg19: chr12-25380244;