rs201170656

chr12-25215446-T-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The ENST00000256078.10(KRAS):c.565A>C(p.Met189Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,613,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: KRAS ENST00000256078.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08682749).
• BP6: Variant 12-25215446-T-G is Benign according to our data. Variant chr12-25215446-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46542.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, not_provided=1, Likely_benign=1, Uncertain_significance=1}. Variant chr12-25215446-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000177 (27/152232) while in subpopulation AMR AF= 0.000262 (4/15286). AF 95% confidence interval is 0.000112. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_033360.4	c.565A>C	p.Met189Leu	missense_variant	5/6	ENST00000256078.10
KRAS	NM_004985.5	c.451-5535A>C		intron_variant		ENST00000311936.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000256078.10	c.565A>C	p.Met189Leu	missense_variant	5/6	1	NM_033360.4	A1
KRAS	ENST00000311936.8	c.451-5535A>C		intron_variant		1	NM_004985.5	P4

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000275 AC: 69 AN: 251164 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135766

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000240 AC: 351 AN: 1460794 Hom.: 0 Cov.: 30 AF XY: 0.000231 AC XY: 168 AN XY: 726804

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74370

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000491 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	KRAS: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:1 Benign:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 14, 2012	The Met189Leu variant in KRAS has not been reported in the literature nor previo usly identified by our laboratory. Computational analyses (biochemical amino aci d properties, conservation, AlignGVGD, PolyPhen2, and SIFT) are either limited f or this position or suggest that the Met189Leu variant may not impact the protei n, though this information is not predictive enough to rule out pathogenicity. F urthermore, this variant has been identified in 0.03% (2/7020) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS/), but this frequency is too low to rule out a d isease causing role. In summary, additional information is needed to fully asses s the clinical significance of the Met189Leu variant. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 07, 2019	Variant summary: KRAS c.565A>C (p.Met189Leu) results in a conservative amino acid change located in the last amino acid of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 278288 control chromosomes (gnomAD), where the observed variant frequency within Ashkenazi Jewish control individuals (0.0022) is approximately 175-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 a benign polymorphism. To our knowledge, no occurrence of c.565A>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant once as benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2015	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. -

KRAS-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	23
Dann	Benign	0.68
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.077
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.45	N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.16	N
REVEL	Uncertain	0.31
Sift	Benign	0.87	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.66
MutPred		0.59		Gain of catalytic residue at K184 (P = 0.0208);
MVP		0.65
MPC		0.062
ClinPred		0.022	T
GERP RS		5.3
Varity_R		0.31
gMVP		0.67

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

Other links and lift over

dbSNP: rs201170656; hg19: chr12-25368380;