chr3-10142088-C-T

Variant names:

• chr3-10142088-C-T
• rs104893829
• NM_000551.4:c.241C>T
• VHL p.Pro81Ser

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_StrongO4_SupportingO5_SupportingO6_SupportingO7_Supporting

The NM_000551.4(VHL):c.241C>T (p.Pro81Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene VHL is a tumor suppressor gene (CancerMine: 345 TSG, 114 oncogene, 46 driver citations). The gene VHL is a known oncogene (CancerMine: 345 TSG, 114 oncogene, 46 driver citations). The gene VHL is a cancer driver gene (CancerMine: 345 TSG, 114 oncogene, 46 driver citations). The variant allele was found at a cumulative frequency of 0.000353 (AC=566) in the gnomAD database across 1,605,226 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.000534. 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 Benign/Likely Benign (★★★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.P81L: Pathogenic/Likely_pathogenic (ClinVar VariationId 36899, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P81A: Uncertain_significance (ClinVar VariationId 1068142, 1 star); p.P81= (synonymous): Benign/Likely_benign (ClinVar VariationId 3468038, 2 stars); p.P81= (synonymous): Benign/Likely_benign (ClinVar VariationId 2927601, 2 stars); p.P81= (synonymous): Benign (ClinVar VariationId 4071324, 1 star) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). The variant has been observed in cBioPortal in 7 samples across 2 studies and 7 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Von hippel-lindau syndrome (vhl); it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Benign reviewed by expert panel P:2 U:12 B:15
• Conservation: PhyloP100: 1.47
• Publications: 51 publications found

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Genomics England PanelApp
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

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

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		CGI exact DNA-change oncogenic — Strong (O1); O1 contributing sources (4.0 pts): CGI (Cancer Genome Interpreter)
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=7 | studies=2 | cancer types=7 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 39 pathogenic, 6 benign (OR vs. background: 30.4); Variant does not impact splicing — splice-hotspot path not applicable

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000551.4. 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
	VHL NM_000551.4	MANE Select	c.241C>T p.Pro81Ser	missense	Exon 1 of 3	Prot: NP_000542.1 UniProt:
	VHL NM_001354723.2		c.241C>T p.Pro81Ser	missense	Exon 1 of 3	Prot: NP_001341652.1 UniProt:
	VHL NM_198156.3		c.241C>T p.Pro81Ser	missense	Exon 1 of 2	Prot: NP_937799.1 UniProt:

VHL NM_000551.4

MANE Select

HGVSc / HGVSpc.241C>Tp.Pro81Ser

Exon rankExon 1 of 3

missense

Prot: NP_000542.1UniProt: A0A024R2F2P40337-1

VHL NM_001354723.2

HGVSc / HGVSpc.241C>Tp.Pro81Ser

Exon rankExon 1 of 3

missense

Prot: NP_001341652.1UniProt: A0A8Q3WL21

VHL NM_198156.3

HGVSc / HGVSpc.241C>Tp.Pro81Ser

Exon rankExon 1 of 2

missense

Prot: NP_937799.1UniProt: P40337-2A0A0S2Z4K1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VHL ENST00000256474.3	TSL:1MANE Select	c.241C>T p.Pro81Ser	missense	Exon 1 of 3	Prot: ENSP00000256474.3 UniProt:
	VHL ENST00000345392.3	TSL:1	c.241C>T p.Pro81Ser	missense	Exon 1 of 2	Prot: ENSP00000344757.2 UniProt:
	VHL ENST00000477538.2	TSL:1	n.287C>T	non_coding_transcript_exon	Exon 1 of 3	Prot:

VHL ENST00000256474.3

TSL:1MANE Select

HGVSc / HGVSpc.241C>Tp.Pro81Ser

Exon rankExon 1 of 3

missense

Prot: ENSP00000256474.3UniProt: P40337-1

VHL ENST00000345392.3

TSL:1

HGVSc / HGVSpc.241C>Tp.Pro81Ser

Exon rankExon 1 of 2

missense

Prot: ENSP00000344757.2UniProt: P40337-2

VHL ENST00000477538.2

TSL:1

HGVSc / HGVSpn.287C>T

Exon rankExon 1 of 3

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000348	AC:53	Hom:0	AN:152206	Cov:33
GnomAD2 exomes	AF: 0.000200	AC:46	Hom:	AN:230188	Cov:
GnomAD4 exome	AF: 0.000353	AC:513	Hom:1	AN:1453020	Cov:32
GnomAD4 genome	AF: 0.000348	AC:53	Hom:0	AN:152206	Cov:33
TOPMed (Bravo)	AF: 0.000348	AC:92	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000598	AC:140	Hom:0	AN:233924	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000390	AC:5	Hom:	AN:12808	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000834 *	8	9598	0.000576 *	6	10410
BipEx(Bipolar disorder (including schizoaffective))	0.000598	17	28420	0.000381	11	28844
Epi25(Epilepsy)	0.000286	12	41958	0.000449	30	66888
SCHEMA(Schizophrenia)	0.000148	18	121784	0.000200	38	190432

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	5	7	Von Hippel-Lindau syndrome (13)
-	2	5	not provided (7)
-	2	1	not specified (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	Chuvash polycythemia (1)
1	-	-	Enchondromatosis (1)
-	1	-	Hepatoblastoma (1)
-	-	1	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.87	D
FuncVEP CTI	Pathogenic	0.71
GPN-Star LLR	N/A	-7.0
GPN-Star score	N/A	7.0
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Pathogenic	0.99	D
Mutation Taster	N/A	7/93	disease causing
MutationAssessor	Benign	1.7	L
PhyloP100	Benign	1.5
popEVE	Benign	-3.2
PrimateAI	Pathogenic	0.88	D
PromoterAI	N/A	-0.042	Neutral
PROVEAN	Uncertain	-3.2	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.68
Sift	Benign	0.038	D
Sift4G	Benign	0.39	T
Varity_R	N/A	0.81
VESM-3B	Benign	-5.7

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs104893829;

hg19: chr3-10183772;

COSMIC: COSV56546019;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar