12-25215476-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000256078.10(KRAS):c.535G>A(p.Gly179Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000254 in 1,611,406 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 3 hom. )

Consequence

KRAS
ENST00000256078.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 4.92

Publications

15 publications found

Variant links:

COSMIC-nc: COSV55638508

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

KRAS links:

LOC124902899 (HGNC:):

LOC124902899 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0101110935).

BP6

Variant 12-25215476-C-T is Benign according to our data. Variant chr12-25215476-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000302 (46/152242) while in subpopulation AMR AF = 0.00137 (21/15294). AF 95% confidence interval is 0.000919. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRAS	NM_004985.5 link	c.451-5565G>A		intron_variant	Intron 4 of 4	ENST00000311936.8	NP_004976.2	P01116-2A0A024RAV5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRAS	ENST00000311936.8 link	c.451-5565G>A		intron_variant	Intron 4 of 4	1	NM_004985.5	ENSP00000308495.3		P01116-2

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000545

AC:

137

AN:

251220

AF XY:

0.000545

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00923

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000249

AC:

363

AN:

1459164

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

169

AN XY:

726200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.000850

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00831

AC:

217

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000568

AC:

AN:

1109742

Other (OTH)

AF:

0.000746

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000302

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41534

American (AMR)

AF:

0.00137

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68008

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000569

Hom.:

Bravo

AF:

0.000385

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Dec 03, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been previously reported in the literature, though it has b een observed by our laboratory in two probands and an individual who is reported ly unaffected with the clinical features of Noonan, LEOPARD, Costello, or Cardio -facio-cutaneous syndromes (NS, LS, CS, CFC). Gly179Ser occurs in exon 5 of KRAS which is an alternatively spliced exon not included in the ubiquitously express ed KRAS transcript B. No variants in exon 5 of KRAS have been proven to be patho genic to date. Two other variants, one missense and one premature stop, have bee n identified in other probands by our laboratory. Neither of these variants have segregated with disease in the families of the probands. Both families with thi s variant are reportedly Hispanic; we have now observed this variant in 2/87 (2. 3%) of Hispanic probands; therefore, this variant could be common in this popula tion. In summary, this variant is likely to be benign. -

Aug 24, 2020

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.535G>A (p.Gly179Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant, Gly179Ser, occurs in exon 5 of KRAS (NM_033360), i.e. in an alternatively spliced exon, not included in the transcript (NM_004985) associated with RASopathy conditions (PMID: 29493581). The variant allele was found at a frequency of 0.00055 in 252582 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 40-fold of 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. To our knowledge, the variant c.535G>A has not been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions and, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

KRAS-related disorder

Benign:1

Sep 23, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Feb 25, 2016

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cardiovascular phenotype

Benign:1

Nov 15, 2021

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

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.12

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.013

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.40

PhyloP100

4.9

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.4

REVEL

Benign

0.15

Sift

Uncertain

0.024

Sift4G

Benign

0.11

Polyphen

0.0010

Vest4

0.43

MVP

0.78

MPC

0.065

ClinPred

0.042

GERP RS

5.6

Varity_R

0.20

gMVP

0.41

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over