NM_000551.3:c.-77C>T meets BA1 (Stand-Alone) under VHL VCEP v1.1.0: GroupMax Filtering Allele Frequency of 8.88% in gnomAD v4.1 far exceeds the BA1 threshold of 0.0156%, establishing this variant as benign.1 NM_000551.3:c.-77C>T also meets BS1 (Strong): GroupMax Filtering Allele Frequency of 8.88% far exceeds the BS1 threshold of 0.00156%, further supporting a benign classification.2 NM_000551.3:c.-77C>T is observed in 332 homozygotes in gnomAD v4.1 and 36 homozygotes in gnomAD v2.1, incompatible with autosomal dominant von Hippel-Lindau disease with high penetrance.3 ClinVar classifies this variant as Benign (Variation ID 256649; 2 clinical laboratories) and Likely benign (1 clinical laboratory).4 No pathogenic or likely pathogenic criteria were met. PM2 was not met (frequency far exceeds PM2_Supporting threshold). PP3 was not met (no computational evidence of deleterious effect). PVS1, PS1, PM1, and PM5 are not applicable to this 5'UTR variant.5 Under VHL VCEP v1.1.0 combination rules (Rule 17), BA1 alone is sufficient for a Benign classification. Overall classification: Benign.6
VHL
Final classification
Benign
VHL c.-77C>T · p.?
VHL
NM_000551.3:c.-77C>T meets BA1 (Stand-Alone) under VHL VCEP v1.1.0: GroupMax Filtering Allele Frequency of 8.88% in gnomAD v4.1 far exceeds the BA1 threshold of 0.0156%, establishing this variant as benign.
ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.1.0 v1.1.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BS1 strong; maps to Benign.
Classification rationale
BA1BS1
Benign
VHL c.-77C>T
BA1 + BS1
→
Benign
Gene diagram
· NM_000551.3 · variants mapped to exon structure
VHL
NM_000551.3
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
Population frequency
332
homozygotes observed in gnomAD v4.1. Healthy biallelic carriers are difficult to reconcile with a fully penetrant loss-of-function disease allele.
Overall AF
7326 / 1,488,092
0.49%
Highest · African/African American
9.1%
Homozygotes
332
grpmax FAF
8.9%
Allele frequency by ancestry — gnomAD v4.1
observed in 6 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| African/African American | 6471 / 71,370 | 9.1% | 325 |
| Admixed American | 320 / 49,082 | 0.65% | 4 |
| Middle Eastern | 9 / 4,228 | 0.21% | 0 |
| European (non-Finnish) | 153 / 1,098,908 | 0.014% | 0 |
| South Asian | 5 / 82,202 | 0.0061% | 0 |
| Ashkenazi Jewish | 1 / 27,836 | 0.0036% | 0 |
| European (Finnish) | 0 / 55,662 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 40,226 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 0.00492308; MAF= 0.49231%, 7326/1488092 alleles, homozygotes = 332) and has highest observed frequency in the African/African American population (AF= 0.0906683; MAF= 9.06683%, 6471/71370 alleles, homozygotes = 325); grpmax FAF= 0.0888216.
36
homozygotes observed in gnomAD v2.1. Healthy biallelic carriers are difficult to reconcile with a fully penetrant loss-of-function disease allele.
Overall AF
805 / 31,292
2.6%
Highest · African/African American
9.1%
Homozygotes
36
grpmax FAF
8.6%
Allele frequency by ancestry — gnomAD v2.1
observed in 4 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| African/African American | 787 / 8,664 | 9.1% | 36 |
| Admixed American | 8 / 848 | 0.94% | 0 |
| Remaining individuals | 7 / 1,086 | 0.64% | 0 |
| European (non-Finnish) | 3 / 15,376 | 0.02% | 0 |
| Ashkenazi Jewish | 0 / 290 | — | — |
| East Asian | 0 / 1,560 | — | — |
| European (Finnish) | 0 / 3,468 | — | — |
| South Asian | 0 / ? | — | — |
“
This variant is present in gnomAD v2.1 (AF= 0.0257254; MAF= 2.57254%, 805/31292 alleles, homozygotes = 36) and has highest observed frequency in the African/African American population (AF= 0.0908356; MAF= 9.08356%, 787/8664 alleles, homozygotes = 36); grpmax FAF= 0.0855752.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 256649)
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV104558409, n = 2 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · 14 PMIDs triaged · 8 high-priority
14papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
25741868 ↗
functional
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PP5PS3PS4
15604628 ↗
case observation
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in
PP5PS4
20664475 ↗
case observation
The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer.
Pheochromocytomas, intra-adrenal paraganglioma, and extra-adrenal sympathetic and parasympathetic paragangliomas are neuroendocrine tumors derived from adrenal chromaffin cells or similar cells in extra-adrenal sympathetic and parasympathetic paraganglia, respectively. Serious morbidity and mortality rates associated with these tumors are related to the potent effects of catecholamines on various
PP5PS4
23788249 ↗
case observation
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the pati
PP5PS4
24319509 ↗
case observation
Canadian guideline on genetic screening for hereditary renal cell cancers.
Hereditary renal cell cancer (RCC) is an ideal model for germline genetic testing. We propose a guideline of hereditary RCC specific criteria to suggest referral for genetic assessment. A review of the literature and stakeholder resources for existing guidelines or consensus statements was performed. Referral criteria were developed by expert consensus. The criteria included characteristics for pa
PP5PS4
25356965 ↗
case observation
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers to help them provide quality medical genetics services. Adherence to these recommendations does not necessarily ensure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedure
PP5PS4
25394175 ↗
case observation
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each pract
PP5PS4
24893135 ↗
background review
Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
PP5PS4
Sources & reference links