ENST00000256078.10:c.540T>A

Variant names:

• chr12-25215471-A-T
• rs373169526
• ENST00000256078.10:c.540T>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_Moderate BP6 BS1 BS2

The ENST00000256078.10(KRAS):​c.540T>A​(p.Cys180*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000208 in 1,611,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: KRAS ENST00000256078.10 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.05
• Publications: 6 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

LOC124902899 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0526 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 12-25215471-A-T is Benign according to our data. Variant chr12-25215471-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46541.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000854 (13/152198) while in subpopulation NFE AF = 0.000147 (10/68022). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5	c.451-5560T>A		intron_variant	Intron 4 of 4	ENST00000311936.8	NP_004976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8	c.451-5560T>A		intron_variant	Intron 4 of 4	1	NM_004985.5	ENSP00000308495.3

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000756 AC: 19 AN: 251200 AF XY: 0.0000663

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000221 AC: 323 AN: 1459674 Hom.: 0 Cov.: 30 AF XY: 0.000209 AC XY: 152 AN XY: 726350

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.0000224 AC: 1 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000276 AC: 306 AN: 1110250

Other (OTH) AF: 0.000182 AC: 11 AN: 60308

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74362

African (AFR) AF: 0.0000724 AC: 3 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Nov 07, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cys180X in exon 5 of KRAS: This variant is not expected to have clinical signifi cance because it has been previously identified by our laboratory in one individ ual who does not have clinical features of Noonan spectrum disorders and a secon d individual who is affected but carries a pathogenic variant in another gene wh ich is likely responsible for the disease. In addition, variants associated with Noonan spectrum disorders are typically gain-of-function; therefore, nonsense v ariants such as this are not common. Furthermore, this variant is located in an exon which is alternatively spliced in one isoform of KRAS. No pathogenic sequen ce variants in this region of the gene have been previously described. This vari ant has also been identified in 0.01% (1/8598) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP r s373169526). In summary, this variant is likely benign. -

Jul 02, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KRAS c.540T>A (p.Cys180X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. However, gain-of-function is the established molecular mechanism for disease for KRAS variants associated with Noonan spectrum disorders. The variant allele was found at a frequency of 7.9e-05 in 276946 control chromosomes (gnomAD). The observed variant frequency is approximately 6-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in KRAS causing Noonan Syndrome and Related Conditions phenotype (1.3e-05), strongly suggesting that the variant is benign. The variant, c.540T>A, has been reported in the literature in an individual presenting with obesity, webbed neck, acne, bilateral inguinal hernia repair, abnormal pubertal development (Bhoj_2016) and an individual presenting with constrictive pericarditis (Herkert_2018) in whom it was classified as "Likely Benign" and "VUS" respectively. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. Another ClinVar submission from a clinical diagnostic laboratory (evaluation before 2014) indicate the variant co-occurred with another pathogenic variant in a different gene and the laboratory classified the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KRAS: BS2 -

Oct 31, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26122175, 29625052, 26689913) -

Cardio-facio-cutaneous syndrome Uncertain:1

Mar 29, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KRAS c.540T>A (p.Cys180X) change is a nonsense variant in an alternate transcript of the KRAS gene that is predicted to cause protein truncation. The disease mechanism for RASopathies is gain-of-function caused by missense changes and protein truncating variants do not have an established correlation to disease (BP1). This variant has a maximum subpopulation frequency of 0.015% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/12-25368405-A-T?dataset=gnomad_r2_1). This is neither rare or greater than expected for the disorder based on thresholds defined by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581). This variant has been reported in an individual with constrictive pericarditis (PMID: 29517769), as well as individuals who do not present with clinical features of RASopathy disorders (PMID: 27763634, internal data). Data deposited into ClinVar indicates that this variant was identified in an individual who is affected by carries a pathogenic variant in another gene which is likely responsible for the disease (ClinVar Accession: SCV000063500.5). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP1. -

Cardiovascular phenotype Benign:1

Jan 31, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.62
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		3.0
Vest4		0.93
GERP RS		5.5
Mutation Taster		=17/183	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs373169526; hg19: chr12-25368405; COSMIC: COSV56090118;