rs397517043

chr12-25209828-TTTC-Tchr12-25209828-TTTC-TTTCTTC

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1 PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_004985.5(KRAS):c.531_533del(p.Lys180del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,610,758 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: KRAS NM_004985.5 inframe_deletion
• Clinical Significance: Benign reviewed by expert panel B:12 O:1
• Conservation: PhyloP100: 7.63

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 -13 ACMG points.

• PM1: In a chain GTPase KRas (size 185) in uniprot entity RASK_HUMAN there are 119 pathogenic changes around while only 1 benign (99%) in NM_004985.5
• PM4: Nonframeshift variant in NON repetitive region in NM_004985.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 12-25209828-TTTC-T is Benign according to our data. Variant chr12-25209828-TTTC-T is described in ClinVar as [Benign]. Clinvar id is 45129.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-25209828-TTTC-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000683 (104/152298) while in subpopulation NFE AF= 0.00126 (86/67992). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRAS	NM_004985.5	c.531_533del	p.Lys180del	inframe_deletion	5/5	ENST00000311936.8
KRAS	NM_033360.4	c.*85_*87del		3_prime_UTR_variant	6/6	ENST00000256078.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRAS	ENST00000311936.8	c.531_533del	p.Lys180del	inframe_deletion	5/5	1	NM_004985.5	P4
KRAS	ENST00000256078.10	c.*85_*87del		3_prime_UTR_variant	6/6	1	NM_033360.4	A1

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000573 AC: 143 AN: 249744 Hom.: 0 AF XY: 0.000578 AC XY: 78 AN XY: 135056

Gnomad AFR exome AF: 0.000497

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00112 AC: 1628 AN: 1458460 Hom.: 2 AF XY: 0.00109 AC XY: 788 AN XY: 725740

Gnomad4 AFR exome AF: 0.000450

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.000631

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74480

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000665

EpiCase AF: 0.000929

EpiControl AF: 0.000949

ClinVar

Significance: Benign

Submissions summary: Benign:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	KRAS: PM4:Supporting, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 21, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

RASopathy Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The filtering allele frequency of the c.531_533delGAA (p.Lys180del) variant in the KRAS gene is 0.51% for European (non-Finnish) chromosomes by the Exome Aggregation Consortium (55/64754 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).This variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM internal data; GTR ID's: 21766, 26957; ClinVar SCV000061947, SCV000207865). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BA1, BP5. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2017	p.Lys180del in exon 6 of KRAS: This variant is not expected to have clinical sig nificance because it has been identified in 0.1% (123/125888) European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs397517043). In addition, it was identified in one individual with featu res of Noonan syndrome who also carried a pathogenic variant in KRAS, which was sufficient to explain their phenotype, and in two parents, one whose disease sta tus was unknown and the other who was unaffected (LMM unpublished data). This va riant causes an in-frame deletion of the amino acid lysine (Lys) at position 180 . This amino acid is in a stretch of six lysine (Lys) residues. -

KRAS-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 30, 2019

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). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2021

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. -

Noonan syndrome and Noonan-related syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

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: rs397517043; hg19: chr12-25362762;