12-25227342-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_004985.5(KRAS):​c.182A>C​(p.Gln61Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 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. Q61H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Failed GnomAD Quality Control

Consequence

KRAS
NM_004985.5 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.00
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a chain GTPase KRas (size 185) 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;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-25227341-T-A is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRASNM_004985.5 linkc.182A>C p.Gln61Pro missense_variant Exon 3 of 5 ENST00000311936.8 NP_004976.2 P01116-2A0A024RAV5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRASENST00000311936.8 linkc.182A>C p.Gln61Pro missense_variant Exon 3 of 5 1 NM_004985.5 ENSP00000308495.3 P01116-2

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152176
Hom.:
0
Cov.:
32
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152176
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74356
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

RASopathy Uncertain:1
Jul 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 61 of the KRAS protein (p.Gln61Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with undergoing clinical exome sequencing (PMID: 27848944). ClinVar contains an entry for this variant (Variation ID: 375966). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KRAS function (PMID: 34117033, 35944066). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.91
.;D
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Pathogenic
3.5
M;M
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.4
D;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
0.99
D;B
Vest4
0.88
MutPred
0.66
Gain of catalytic residue at A59 (P = 0);Gain of catalytic residue at A59 (P = 0);
MVP
0.97
MPC
3.0
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.99
gMVP
0.98

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913240; hg19: chr12-25380276; COSMIC: COSV55508574; COSMIC: COSV55508574; API