chr3-10142088-CCG-TCT

Variant names:

• chr3-10142088-CCG-TCT
• NM_000551.4:c.241_243delCCGinsTCT
• VHL p.Pro81Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO5_ModerateO7_SupportingB2_Supporting

The NM_000551.4(VHL):c.241_243delCCGinsTCT (p.Pro81Ser) variant causes a missense change. 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). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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); p.P81S: Benign (ClinVar VariationId 2233, 3 stars) The same amino acid change has been reported as oncogenic or likely oncogenic in a clinical somatic variant database. 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: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• Publications: 0 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: Uncertain_significance. The variant received 4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O5Same location/impact as known oncogenic		Same AA change as established oncogenic variant (or germline P/LP in TSG) — Moderate (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: true | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	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
	B2Does not fit gene mode of action		Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context); Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context)

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.241_243delCCGinsTCT p.Pro81Ser	missense	N/A	Prot: NP_000542.1 UniProt:
	VHL NM_001354723.2		c.241_243delCCGinsTCT p.Pro81Ser	missense	N/A	Prot: NP_001341652.1 UniProt:
	VHL NM_198156.3		c.241_243delCCGinsTCT p.Pro81Ser	missense	N/A	Prot: NP_937799.1 UniProt:

VHL NM_000551.4

MANE Select

HGVSc / HGVSpc.241_243delCCGinsTCTp.Pro81Ser

Exon rankN/A

missense

Prot: NP_000542.1UniProt: A0A024R2F2P40337-1

VHL NM_001354723.2

HGVSc / HGVSpc.241_243delCCGinsTCTp.Pro81Ser

Exon rankN/A

missense

Prot: NP_001341652.1UniProt: A0A8Q3WL21

VHL NM_198156.3

HGVSc / HGVSpc.241_243delCCGinsTCTp.Pro81Ser

Exon rankN/A

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.241_243delCCGinsTCT p.Pro81Ser	missense	N/A	Prot: ENSP00000256474.3 UniProt:
	VHL ENST00000345392.3	TSL:1	c.241_243delCCGinsTCT p.Pro81Ser	missense	N/A	Prot: ENSP00000344757.2 UniProt:
	VHL ENST00000477538.2	TSL:1	n.287_289delCCGinsTCT	non_coding_transcript_exon	Exon 1 of 3	Prot:

VHL ENST00000256474.3

TSL:1MANE Select

HGVSc / HGVSpc.241_243delCCGinsTCTp.Pro81Ser

Exon rankN/A

missense

Prot: ENSP00000256474.3UniProt: P40337-1

VHL ENST00000345392.3

TSL:1

HGVSc / HGVSpc.241_243delCCGinsTCTp.Pro81Ser

Exon rankN/A

missense

Prot: ENSP00000344757.2UniProt: P40337-2

VHL ENST00000477538.2

TSL:1

HGVSc / HGVSpn.287_289delCCGinsTCT

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	2.2

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr3-10183772;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar