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SDHB
Final classification
VUS
SDHB c.172A>G · p.Met58Val
SDHB

NM_003000.3:c.172A>G (p.Met58Val) is a missense variant in SDHB, a tumor suppressor gene associated with autosomal dominant hereditary pheochromocytoma-paraganglioma.

Gene
SDHB
Transcript
NM_003000.3
HGVS · transcript:coding
NM_003000.3:c.172A>G
Consequence
N/A
GRCh38
chr1:17044789 T>C
GRCh37
chr1:17371284 T>C
Basis ClinGen Endocrine Tumor Predisposition Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SDHB Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
ClinGen Endocrine Tumor Predisposition Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SDHB Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2 VUS
SDHB c.172A>G

NM_003000.3:c.172A>G (p.Met58Val) is a missense variant in SDHB, a tumor suppressor gene associated with autosomal dominant hereditary pheochromocytoma-paraganglioma.1 This variant is absent from gnomAD v2.1 and v4.1, supporting PM2 at supporting level per generic ACMG/AMP 2015 criteria.2 Six clinical laboratories have submitted this variant to ClinVar, all classifying it as Uncertain Significance (ClinVar variation ID: 459138).3 In silico predictions are indeterminate: SpliceAI predicts no splice impact (max delta 0.00) and BayesDel score is 0.338, which does not reach a pathogenic or benign threshold. REVEL score is unavailable.4 No functional studies, case reports, segregation data, or de novo observations have been identified for this variant in the reviewed literature or curated databases.5 No pathogenic missense variant at the same amino acid residue (Met58) was identified for PM5 comparison.6 The ClinGen Endocrine Tumor Predisposition Expert Panel specifications for SDHB (version 1.0.0) were identified but contained no parsed criterion-level rules; classification adheres to generic ACMG/AMP 2015 framework.7 With only PM2_Supporting met and no additional pathogenic or benign criteria satisfied, the variant remains a Variant of Uncertain Significance per ACMG/AMP 2015 combination rules (PMID:25741868).8

PM2 VUS
4 spliceai ↗bayesdel
6 pm5_candidates
7 cspec ↗generic_acmg_combination_rules
8 generic_acmg_combination_rules
Gene diagram · NM_003000.3 · variants mapped to exon structure
SDHB NM_003000.3
Fetching transcript structure from UCSC…
Applied criteria · 1 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
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      Population frequency
      Absent from gnomAD v4.1.
      Absent from gnomAD v2.1.
      This variant is absent from gnomAD-Canada.
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 459138)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.338173.
      Functional / OncoKB screenshot
      Functional Unknown Oncogenic Effect
      OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SDHB, a subunit of succinate dehydrogenase, is infrequently altered in cancer.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Not in COSMIC / hotspots
      COSMIC
      This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      Literature · 21 PMIDs triaged · 8 high-priority
      21papers 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.
      20816580 ↗ splicing rna
      Endocrine cancer predisposition syndromes: hereditary paraganglioma, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2, and hereditary thyroid cancer.
      The hereditary paraganglioma, MEN1, MEN2, and hereditary thyroid cancer syndromes are clinically discernable and genetically distinct. The first 3 syndromes have been well characterized in the past 10 to 15 years. Recognizing these 3 syndromes and using a multidisciplinary team approach creates valuable opportunities for early diagnosis, reduction of morbidity and mortality, and avoidance of surgi
      BP7PP3PP5PS4PVS1
      23852704 ↗ functional
      Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.
      Biomarkers currently play an important role in the detection and management of patients with several different types of gastrointestinal cancer, especially colorectal, gastric, gastro-oesophageal junction (GOJ) adenocarcinomas and gastrointestinal stromal tumors (GISTs). The aim of this article is to provide updated and evidence-based guidelines for the use of biomarkers in the different gastroint
      BS3PP5PS3PS4
      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
      20065170 ↗ case observation
      American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
      PP5PS4
      20301715 ↗ case observation
      Untitled reference
      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
      22685257 ↗ background review
      The UK NEQAS for Molecular Genetics scheme for gastrointestinal stromal tumour: findings and recommendations following four rounds of circulation.
      PP5PS4
      24893135 ↗ background review
      Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
      PP5PS4
      28492532 ↗ background review
      Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
      PS3PS4
      33939658 ↗ background review
      The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.
      PP5PS4
      Sources & reference links
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots