12-25227376-T-C

Variant names:

• chr12-25227376-T-C
• rs730880470
• NM_033360.4:c.148A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_033360.4(KRAS):​c.148A>G​(p.Thr50Ala) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T50I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRAS NM_033360.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_033360.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-25227375-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 984504.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_033360.4	c.148A>G	p.Thr50Ala	missense_variant	Exon 3 of 6	ENST00000256078.10	NP_203524.1
KRAS	NM_004985.5	c.148A>G	p.Thr50Ala	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	ENST00000256078.10	c.148A>G	p.Thr50Ala	missense_variant	Exon 3 of 6	1	NM_033360.4	ENSP00000256078.5
KRAS	ENST00000311936.8	c.148A>G	p.Thr50Ala	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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

RASopathy Uncertain:1

May 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 50 of the KRAS protein (p.Thr50Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant has not been reported in the literature in individuals with KRAS-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	.;D
Eigen	Benign	0.046
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.2	L;L
PhyloP100		8.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.41
Sift	Benign	0.049	D;D
Sift4G	Benign	0.82	T;T
Polyphen		0.016	B;B
Vest4		0.80
MutPred		0.51		Gain of catalytic residue at L52 (P = 2e-04);Gain of catalytic residue at L52 (P = 2e-04);
MVP		0.86
MPC		1.5
ClinPred		0.85	D
GERP RS		5.6
Varity_R		0.75
gMVP		0.84
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs730880470; hg19: chr12-25380310; COSMIC: COSV56083443;