Risk stratification of variants of unknown significance (VUS) in monogenic endocrine tumour genes using population-level genetic data and computational analysis

Pathologists using their routine diagnostic tools can contribute both to the care of patients with pheochromocytoma/paraganglioma and to understanding the pathobiology of the tumors. They can document details of tissue organization and cytology that are accessible only by microscopy and can characterize admixtures of cell types that are morphologically distinct or show differential expression of immunohistochemical markers. Current roles and challenges for pathologists include differential diagnosis, identifying clues to the presence of hereditary disease, and effective communication of pathology information for clinical and research purposes. Future roles will increasingly involve risk stratification, identification of actionable targets for personalized therapies, and aiding the interpretation of molecular tests by helping characterize genetic variants of unknown significance. It remains to be determined to what extent the need for pathology input will be overshadowed by the availability of genetic testing and other molecular analyses at ever-decreasing cost, together with very effective clinical paradigms for risk stratification and patient care.

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Predicting the Functional Impact of KCNQ1 Variants of Unknown Significance

Circulation Cardiovascular Genetics ◽

10.1161/circgenetics.117.001754 ◽

2017 ◽

Vol 10 (5) ◽

Cited By ~ 15

Author(s):

Bian Li ◽

Jeffrey L. Mendenhall ◽

Brett M. Kroncke ◽

Keenan C. Taylor ◽

Hui Huang ◽

...

Keyword(s):

Functional Impact ◽

Variants Of Unknown Significance ◽

Unknown Significance

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SAT0531 NEXT GENERATION SEQUENCING AND AUTOINFLAMMATORY SYNDROMES: CLINICAL AND GENETICAL CORRELATION ON AN ADULT POPULATION FROM A REFERRAL THIRD-CARE CENTRE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.5067 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1223-1223

Author(s):

J. R. Marques Soares ◽

M. Antolin Mate ◽

E. Garcia Arumi ◽

E. Tizzano Ferrari ◽

S. Bujan Rivas

Keyword(s):

Next Generation Sequencing ◽

Genetic Data ◽

Clinical Suspicion ◽

Gene Panel ◽

Adult Patients ◽

Next Generation ◽

Related Gene ◽

Unknown Significance ◽

Level Hospital ◽

Generation Sequencing

Background:Systemic autoinflammatory diseases (sAID) are a group of conditions with recurrent episodes of inflammation in absence of infection or autoimmune response. Its physiopathology mainly lies on mono/poligenic mutations involving genes related to the innate immune system response. Next Generation Sequencing (NGS) platformss have been a big step forward on sAID diagnosis, although a clinical and genetic correlation is still needed.Objectives:To review the sAID related gene panel variants identified using NGS sAID gene panel on a cohort of adult patients screened for sAID from a referral third-level hospital.To correlate genetic and clinical findings for sAID related variants identified in order to the clinical suspicion diagnosis of sAID.Methods:A retrospective review of a cohort of adult (≥ 16 yo) patients with available NGS sAID related gene panel (MiSeq Illumina sequencing platform including intron and exon variants from up to 17 sAID genes, with coverage depth > x100) among 2014 and 2019 was performed.Demographic, clinical and genetic data were collected in a database.Genetic variants were classified according to the American College of Medical Genetics/Association for Molecular Pathology classification as benign/likely benign/variable of unknown significance (VUS)/likely pathogenic/pathogenic. In case of polymorphisms or lack of genetic data, the variants were named as unclassified.A description of the cohort and an analysis of the correlation assessment between clinical data and genetic findings were performed.Results:246 out of 299 (82%) patients with NGS sAID gene panel had clinical data available. 170/246 (69%) were adult patients. The medium age was 48 yo, and the M/F ratio was 2.46. 87/170 (51%) adult patients presented 122 variants involving sAID genes (60/87 patients with a single variant). All the variants out of 7 seven were heterozygous variants.Variants were classified according to ACMG/AMP as follow: pathogenic/probably pathogenic: 22/122 (18%), unknown significance: 74/122 (60.6%), benign/probably benign: 6/122 (4.91%). 20/122 (16.4%) were unclassified variants or polymorphisms.The most frequent variants identified involved MEFV (54/122), NOD2/CARD15 (18/122) and TNFRSF1A (17/122 including 12 p.Arg121Gln variants) genes.37/122 (30%) variants correlated with the clinical picture in 33 patients, allowing to confirm the suspected diagnosis. Among the 122 variants, 7 not previously communicated variants were identified.No somatic variants were found.Conclusion:NGS sAID related gene panel is a useful tool for sAID diagnosis. In this cohort of 170 adult patients from a referral third-level hospital, genetic tests identified sAID related variants in almost half of them.20% of patients who underwent genetic NGS sAID related gene panel studies were finally diagnosed with sAID.The identification of a genetic variant (even pathogenic / likely pathogenic variant) is not diagnostic for sAID if there is not a suggestive clinical picture.Despite genetic findings, a careful evaluation of clinical – genetic correlation is needed to confirm the suspicion diagnosis, especially for low penetrance variants like TNFRSF1A p. Arg121Gln.References:Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study. Karacan I, Balamir A, Uğurlu S, et al. . Rheumatol Int. 2019 May;39(5):911-919. doi: 10.1007/s00296-019-04252-5. Epub 2019 Feb 19.Disclosure of Interests:None declared

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Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the VHL Mutation p.P81S (c.241C>T)

Current Genomics ◽

10.2174/1389202917666160805153221 ◽

2016 ◽

Vol 18 (1) ◽

pp. 93-103

Author(s):

Daniela Alosi ◽

Marie Bisgaard ◽

Sophie Hemmingsen ◽

Lotte Krogh ◽

Hanne Mikkelsen ◽

...

Keyword(s):

Risk Assessment ◽

Gene Variants ◽

Analysis Method ◽

Variants Of Unknown Significance ◽

Significance Analysis ◽

Unknown Significance

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Very Elevated IgE, Atopy, and Severe Infection: A Genomics-Based Diagnostic Approach to a Spectrum of Diseases

Case Reports in Immunology ◽

10.1155/2021/2767012 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

A. Chin ◽

S. Balasubramanyam ◽

C. M. Davis

Keyword(s):

Autosomal Dominant ◽

Severe Infection ◽

Severe Atopic Dermatitis ◽

Genomic Testing ◽

Atopic Diseases ◽

Variants Of Unknown Significance ◽

Hyper Ige Syndrome ◽

Heterozygous Variant ◽

Unknown Significance ◽

Multiple Variants

Elevated IgE has been long recognized as an important clinical marker of atopy but can be seen in a myriad of conditions. The discovery of autosomal dominant STAT3 deficiency marked the first recognition of hyper-IgE syndrome (HIES) and the first primary immunodeficiency linked to elevated IgE. Since then, genomic testing has increased the number of defects with associated mutations causing hyper-IgE syndrome and atopic diseases with FLG, DOCK8, SPINK5, and CARD11, among others. A spectrum of recurrent infections and atopy are hallmarks of elevated IgE with significant phenotypic overlap between each underlying condition. As treatment is predicated on early diagnosis, genomic testing is becoming a more commonly used diagnostic tool. We present a 6-year-old male patient with markedly elevated IgE and severe atopic dermatitis presenting with staphylococcal bacteremia found to have a heterozygous variant in FLG (p.S3247X) and multiple variants of unknown significance in BCL11B, ZAP70, LYST, and PTPRC. We review the genetic defects underpinning elevated IgE and highlight the spectrum of atopy and immunodeficiency seen in patients with underlying mutations. Although no one mutation is completely causative of the constellation of symptoms in this patient, we suggest the synergism of these variants is an impetus of disease.

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A computational and structural analysis of germline and somatic variants affecting the DDR mechanism, and their impact on human diseases

Scientific Reports ◽

10.1038/s41598-021-93715-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lorena Magraner-Pardo ◽

Roman A. Laskowski ◽

Tirso Pons ◽

Janet M. Thornton

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Dna Damage Response ◽

Protein Interaction ◽

Three Dimensional ◽

Protein Protein Interaction ◽

Variants Of Unknown Significance ◽

Damage Response ◽

Dna Variants ◽

Unknown Significance

AbstractDNA-Damage Response (DDR) proteins are crucial for maintaining the integrity of the genome by identifying and repairing errors in DNA. Variants affecting their function can have severe consequences since failure to repair damaged DNA can result in cells turning cancerous. Here, we compare germline and somatic variants in DDR genes, specifically looking at their locations in the corresponding three-dimensional (3D) structures, Pfam domains, and protein–protein interaction interfaces. We show that somatic variants in metastatic cases are more likely to be found in Pfam domains and protein interaction interfaces than are pathogenic germline variants or variants of unknown significance (VUS). We also show that there are hotspots in the structures of ATM and BRCA2 proteins where pathogenic germline, and recurrent somatic variants from primary and metastatic tumours, cluster together in 3D. Moreover, in the ATM, BRCA1 and BRCA2 genes from prostate cancer patients, the distributions of germline benign, pathogenic, VUS, and recurrent somatic variants differ across Pfam domains. Together, these results provide a better characterisation of the most recurrent affected regions in DDRs and could help in the understanding of individual susceptibility to tumour development.

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Additive effects of variants of unknown significance in replication repair-associated DNA polymerase genes on mutational burden and prognosis across diverse cancers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002336 ◽

2021 ◽

Vol 9 (9) ◽

pp. e002336

Author(s):

Jieer Ying ◽

Lin Yang ◽

Jiani C Yin ◽

Guojie Xia ◽

Minyan Xing ◽

...

Keyword(s):

Hot Spot ◽

The Cancer Genome Atlas ◽

Driver Mutations ◽

Cancer Type ◽

Additive Effects ◽

Variants Of Unknown Significance ◽

Mutational Burden ◽

Pathway Gene ◽

Exonuclease Domain ◽

Unknown Significance

BackgroundDefects in replication repair-associated DNA polymerases often manifest an ultra-high tumor mutational burden (TMB), which is associated with higher probabilities of response to immunotherapies. The functional and clinical implications of different polymerase variants remain unclear.MethodsTargeted next-generation sequencing using a 425-cancer gene panel, which covers all exonic regions of three polymerase genes (POLE, POLD1, and POLH), was conducted in a cohort of 12,266 patients across 16 different tumor types from January 2017 to January 2019. Prognostication of POL variant-positive patients was performed using a cohort of 4679 patients from the The Cancer Genome Atlas (TCGA) datasets.ResultsThe overall prevalence of somatic and germline polymerase variants was 4.2% (95% CI 3.8% to 4.5%) and 0.7% (95% CI 0.5% to 0.8%), respectively, with highest frequencies in endometrial, urinary, prostate, and colorectal cancers (CRCs). While most germline polymerase variants showed no clear functional consequences, we identified a candidate p.T466A affecting the exonuclease domain of POLE, which might be underlying the early onset in a case with childhood CRC. Low frequencies of known hot-spot somatic mutations in POLE were detected and were associated with younger age, the male sex, and microsatellite stability. In both the panel and TCGA cohorts, POLE drivers exhibited high frequencies of alterations in genes in the DNA damage and repair (DDR) pathways, including BRCA2, ATM, MSH6, and ATR. Variants of unknown significance (VUS) of different polymerase domains showed variable penetrance with those in the exonuclease domain of POLE and POLD1 displaying high TMB. VUS in POL genes exhibited an additive effect as carriers of multiple VUS had exponentially increased TMB and prolonged overall survival. Similar to cases with driver mutations, the TMB-high POL VUS samples showed DDR pathway involvement and polymerase hypermutation signatures. Combinatorial analysis of POL and DDR pathway status further supported the potential additive effects of POL VUS and DDR pathway genes and revealed distinct prognostic subclasses that were independent of cancer type and TMB.ConclusionsOur results demonstrate the pathogenicity and additive prognostic value of POL VUS and DDR pathway gene alterations and suggest that genetic testing may be warranted in patients with diverse solid tumors.

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Clinical Impact of Rare Variants Associated with Inherited Channelopathies: A Five-Year Update

10.21203/rs.3.rs-369063/v1 ◽

2021 ◽

Author(s):

georgia sarquella ◽

Anna Fernandez ◽

sergi cesar ◽

elena arbelo ◽

monica coll ◽

...

Keyword(s):

Rare Variants ◽

Genetic Data ◽

Clinical Impact ◽

Clinical Translation ◽

Clinical Implications ◽

Frequency Data ◽

Unknown Significance ◽

Common Group ◽

Genetics And Genomics ◽

Proper Interpretation

Abstract A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified five years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics’ recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included fourty-nine cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After five years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than five years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified.

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