chr11-534289-C-A

Variant names:

• chr11-534289-C-A
• rs104894229
• NM_005343.4:c.34G>T
• HRAS p.Gly12Cys

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019): 12P and 0B. PS3PM2PP3_ModeratePP5_Strong

The NM_001318054.2(HRAS):c.-286G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001448594: "In functional studies, Niihori et al (Niihori_2011) report that there was an increase in guanosine triphosphate (GTP)-bound HRAS and activation of RAS signaling pathway (as measured by the activation of ELK1 and c-Jun) in cells transfected with the variant of interest." Niihori_2011" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.G12A: Pathogenic (ClinVar VariationId 40430, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G12= (synonymous): Likely_benign (ClinVar VariationId 222076, 3 stars); p.G12= (synonymous): not_provided (ClinVar VariationId 177957) This variant is listed in the SVIG-UK Canonical Variants List — a curated registry of well-established oncogenic variants (O1 criterion, stand-alone Oncogenic). This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 63 samples carry this exact amino acid change out of 441 samples with a variant at this residue. This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 34)
• Consequence: HRAS NM_001318054.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17 O:1
• Conservation: PhyloP100: 6.09
• Publications: 181 publications found

Genes affected

HRAS (HGNC:5173): (HRas proto-oncogene, GTPase) This gene belongs to the Ras oncogene family, whose members are related to the transforming genes of mammalian sarcoma retroviruses. The products encoded by these genes function in signal transduction pathways. These proteins can bind GTP and GDP, and they have intrinsic GTPase activity. This protein undergoes a continuous cycle of de- and re-palmitoylation, which regulates its rapid exchange between the plasma membrane and the Golgi apparatus. Mutations in this gene cause Costello syndrome, a disease characterized by increased growth at the prenatal stage, growth deficiency at the postnatal stage, predisposition to tumor formation, cognitive disability, skin and musculoskeletal abnormalities, distinctive facial appearance and cardiovascular abnormalities. Defects in this gene are implicated in a variety of cancers, including bladder cancer, follicular thyroid cancer, and oral squamous cell carcinoma. Multiple transcript variants, which encode different isoforms, have been identified for this gene. [provided by RefSeq, Jul 2008]

LRRC56 (HGNC:25430): (leucine rich repeat containing 56) Predicted to be involved in cell projection organization. Predicted to be located in cilium. Implicated in primary ciliary dyskinesia 39. [provided by Alliance of Genome Resources, Apr 2022]

LRRC56 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 39

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for HRAS are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 12 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV001448594: "In functional studies, Niihori et al (Niihori_2011) report that there was an increase in guanosine triphosphate (GTP)-bound HRAS and activation of RAS signaling pathway (as measured by the activation of ELK1 and c-Jun) in cells transfected with the variant of interest." Niihori_2011; SCV003253337: Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009).; SCV000207843: Published functional studies of the G12C variant have shown that it results in increased active, GTP-bound HRAS (Niihori et al., 2011); SCV004562717: Functional characterization of the p.Gly12Cys protein indicates increased downstream MEK signaling activity (Niihori 2011), consistent with the established disease mechanism of Costello syndrome. PMID: 21850009
• PM2: Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• PP5: ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001318054.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.34G>T	p.Gly12Cys	missense	Exon 2 of 6	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.34G>T	p.Gly12Cys	missense	Exon 2 of 6	NP_789765.1	P01112-2
	HRAS	NM_001318054.2		c.-286G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_001304983.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.34G>T	p.Gly12Cys	missense	Exon 2 of 6	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.34G>T	p.Gly12Cys	missense	Exon 2 of 6	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.34G>T		non_coding_transcript_exon	Exon 2 of 7	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Costello syndrome (8)
4	-	-	not provided (4)
2	-	-	Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0587248:Costello syndrome;C1842036:Large congenital melanocytic nevus;C4225426:Thyroid cancer, nonmedullary, 2;C4552097:Linear nevus sebaceous syndrome (2)
1	-	-	Epidermal nevus (1)
1	-	-	Nevus sebaceous (1)
1	-	-	RASopathy (1)
-	-	-	Embryonal rhabdomyosarcoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.024	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104894229;

hg19: chr11-534289;

COSMIC: COSV54236828;

COSMIC: COSV54236828;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar