Submissions for variant NM_000551.4(VHL):c.98C>A (p.Ser33Ter)

gnomAD frequency: 0.00001  dbSNP: rs1476994915

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792429	SCV000931727	uncertain significance	Chuvash polycythemia; Von Hippel-Lindau syndrome	2022-10-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser33*) in the VHL gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 639599). Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001019872	SCV001181284	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-19	criteria provided, single submitter	clinical testing	The p.S33* variant (also known as c.98C>A), located in coding exon 1 of the VHL gene, results from a C to A substitution at nucleotide position 98. This changes the amino acid from a serine to a stop codon within coding exon 1. This alteration was detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). Premature stop codons are typically deleterious in nature; however, an alternate initiation codon exists 21 residues downstream from this alteration, and is reported to result in a biologically active isoform known as VHL19 (Iliopoulos O et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Sep; 95(20):11661-6; Schoenfeld A et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Jul; 95(15):8817-22). Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV004527399	SCV005038975	uncertain significance	Von Hippel-Lindau syndrome	2024-05-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser33*) in the VHL gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 639599). Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). The available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.