12-25227345-C-A

Variant names:

• chr12-25227345-C-A
• rs727503108
• NM_004985.5:c.179G>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_004985.5(KRAS):​c.179G>T​(p.Gly60Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G60R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KRAS NM_004985.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.89
• Publications: 25 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 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain 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 chr12-25227346-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 12586.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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: 3.0857 (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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 12-25227345-C-A is Pathogenic according to our data. Variant chr12-25227345-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 163766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.179G>T	p.Gly60Val	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	ENST00000311936.8	c.179G>T	p.Gly60Val	missense_variant	Exon 3 of 5	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251328 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461824 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000192 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Sep 13, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 20926413, 28639239, 33142350, 24382853, 23548132, 34958143, 19396835, 30732632, 16474404, 26242988) -

Jan 23, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PM1, PM2, PM5, PS2, PS4 -

Oct 26, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1

Jul 19, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The Gly60Val variant in KRAS has not been previously identified in our laborator y, nor has this specific variant been reported in the literature in individuals with clinical features of Noonan spectrum disorders. However, two different amin o acid changes at the same codon, Gly60Arg and Gly60Ser, have been reported in t wo individuals with Cardio-facio-cutaneous syndrome and Noonan syndrome, respect ively (CFC; Niihori 2006, Kratz 2009). Parental testing confirmed the Gly60Ser h ad occured de novo in that patient (Kratz 2009). This variant has been observed to occur as a somatic change in two metastatic colorectal cancer tissues and ot her variants at this codon have been identified as somatic changes in other tiss ue types (Okayama 2011, Guedes 2013, COSMIC database). Functional studies sugges t the Gly60 is an important residue since it interacts with ?-phosphate of GTP a nd is a conserved amino acid across the superfamily of GTPases (Guedes 2013). Fu rthermore, this variant was absent in large, ethnically-distinct populations. Co mputational analyses (biochemical amino acid properties, conservation, AlignGVGD , PolyPhen2, and SIFT) suggest that the Gly60Val variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant is likely pathogenic, though additional studies are requi red to fully establish its clinical significance. -

Non-small cell lung carcinoma Pathogenic:1

Jul 19, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy Pathogenic:1

Jul 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 163766). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 60 of the KRAS protein (p.Gly60Val). This variant is present in population databases (rs727503108, gnomAD 0.0009%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 24382853). In at least one individual the variant was observed to be de novo. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly60 amino acid residue in KRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19396835, 30732632). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.4	D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.79		Gain of catalytic residue at E63 (P = 0.0237);Gain of catalytic residue at E63 (P = 0.0237);
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs727503108; hg19: chr12-25380279; COSMIC: COSV55708344;