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A variant of uncertain (or unknown) significance (VUS) is a genetic variant that has been identified through genetic testing but whose significance to the function or health of an organism is not known. Two related terms are "gene of uncertain significance" (GUS), which refers to a gene that has been identified through genome sequencing but whose connection to a human disease has not been established, and "insignificant mutation", referring to a gene variant that has no impact on the health or function of an organism. The term "variant' is favored in clinical practice over "mutation" because it can be used to describe an allele more precisely (i.e. without inherently connoting pathogenicity). When the variant has no impact on health, it is called a "benign variant". When it is associated with a disease, it is called a "pathogenic variant". A "pharmacogenomic variant" has an effect only when an individual takes a particular drug and therefore is neither benign nor pathogenic. A VUS is most commonly encountered by people when they get the results of a lab test looking for a mutation in a particular gene. For example, many people know that mutations in the BRCA1 gene are involved in the development of breast cancer because of the publicity surrounding Angelina Jolie's preventative treatment. Few people are aware of the immense number of other genetic variants in and around BRCA1 and other genes that may predispose to hereditary breast and ovarian cancer. A recent study of the genes ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2 and TP53 found 15,311 DNA sequence variants in only 102 patients. Many of those 15,311 variants have no significant phenotypic effect. That is, a difference can be seen in the DNA sequence, but the differences have no effect on the growth or health of the person. Identifying variants that are significant or likely to be significant is a difficult task that may require expert human and in silico analysis, laboratory experiments and even information theory. In spite of those efforts, many people may be worried about their particular VUS, even though it has not been determined to be significant or likely to be significant. Most discovered VUSs will not be investigated in a peer-reviewed research paper, as this effort is usually reserved for likely pathogenic variants. History In 2001, an initial draft of the human genome was published by the International Human Genome Sequencing Consortium. With the development of next-generation sequencing, the cost of sequencing has plummeted and the number of human genomes and exomes sequenced each year is increasing dramatically. As of 2017, the cost of a quality whole genome sequence is $1,000 or less. If the ratio of approximately 20 DNA sequence variants per gene holds over the entire genome (with approximately 20,000 genes) that means that every person who elects to have their genome sequenced will be provided with almost half a million Variants of Unknown Significance. To assist people to understand the meaning of all these variants, classification is a first step. Classification In 2015, the American College of Medical Genetics and Genomics (ACMG), the Association for Molecular Pathology (AMP), and the College of American Pathologists (CAP) published a third revision of their guidelines on variant interpretation in Mendelian disorders. The publication recommended the following categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. This guideline is one of many resources published by the ACMG in hopes of improving standardization of variant interpretation and reporting. As of 2020, there continues to be limited involvement from federal agencies to regulate the clinical validity (accuracy) and utility (risks and benefits) of genetic testing. Variant interpretation and classification is notably subjective, as laboratories developed their own criteria prior to the ACMG-AMP guidelines. This subjectiveness is further problematic when there is evidence that variant significance changes over time. Due to the lack of consistency in official guidelines, the genomics community is left struggling to efficiently categorize genetic variants. Pathogenic This category is for variants that are well-documented to cause disease. Likely pathogenic This category is for variants where the evidence is compelling, but not definitive, to cause disease. Uncertain significance This category is for variants where there is unknown or conflicting clinical significance. Additional evidence is needed in order to determine whether or not the variant is causative for a particular disease. Likely benign This category is for variants that are not causative for a disease. Benign This category is for variants that are not causative for a disease. Benign variants are usually seen previously in higher frequencies and in silico analysis predicts a benign effect on the encoded protein. Limitations of the classifications Less than 5% of the human genome encodes proteins, and the rest is associated with non-coding RNA molecules, regulatory DNA sequences, LINEs, SINEs, introns, and sequences for which as yet no function has been determined. Thus, only a small fraction of the almost half-million VUS's that are expected to be identified by whole genome sequencing can be categorized into the 5 categories above, leaving the patient nearly as uninformed about their variants as they would have been without this information. Most of the base sequences regulating gene expression are found outside of protein-coding sequences, either within introns or outside of genes in intergenic regions. Changes in those regulatory regions can lead to dysfunction of a gene(s) and produce phenotypic effects that can be relevant to health and function. An example of a variant in an intergenic enhancer is one that is associated with blond hair color in northern Europeans. The variant in an enhancer of the KITLG gene causes only a 20% change in gene expression, yet causes hair lightening. An example of an intronic VUS controlling gene expression is the SNP found in an intron of the FTO gene. The FTO gene encodes the fat mass and obesity-associated protein, and the SNP (or VUS) found in its intron was shown by genome-wide association studies to be associated with an increased risk for obesity and diabetes. The initial assumption was that this mutation was misregulating FTO to cause the disease risk. However, it was later shown that the intronic variant was in fact regulating the distant IRX3 gene and not the FTO gene. That is just one example of how difficult it can be to determine the significance of a VUS even when many research labs are focused on it, and it illustrates that clinicians cannot reliably interpret genetic results that have not been fully clarified by prior research. Applications The number of VUS reports makes it impossible to mention all such reports. To give a flavor for some applications in one field, it is perhaps of m.... Discover the Gene Bedell popular books. Find the top 100 most popular Gene Bedell books.
Best Seller Gene Bedell Books of 2024
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Pretty Little Lies
Ivy ThornFour years ago, Nicolo Marchetti took my innocence. But he left me with something else Nicolo almost took everything from me. My virginity, my reputation, and very nearly my future...
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The Icing on the Cake
Linda SeedShe’s a baker without a kitchen. He’s got a double oven to spare. It’s a recipe for success, until his mother starts stirring up trouble … Cassie Jordan has a sweet dream to open a...
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Once Upon A One-Night Stand
Zoey LockeAt first sight, there was electrifying chemistry.  So why not go for it? After all, Lynx Grove, the city's most eligible bachelor, wants to claim her, at least for th...
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The Holy Bible - King James Version
King JamesHoly Bible King James Version Few Sample Paragraphs from The Holy Bible eBook, Genesis (OT) 1 Gen. 1 IN the beginning God created the heaven and the earth. 2 And the earth was with...
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Masters of Restraint
Ines JohnsonMy new boss is good at giving orders. But his latest demand is NSFW. Especially when his two business partners want in on our deal. My new boss My boss’s boss Their investor &#...
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Meditations
Emperor of Rome Marcus AureliusMeditations is a series of personal writings by Marcus Aurelius, Roman Emperor 161–180 CE, setting forth his ideas on Stoic philosophy.
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Salvation
Meghan O'FlynnIf you like mouthy detectives, serial killers, and suspenseful mysteries that don't quit, this chilling and actionpacked hardboiled detective series has you covered! Try this ...
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Little Women
Louisa May AlcottAn Apple Books Classic edition. Meet the Marches! Louisa May Alcott’s classic introduces us to four unforgettable sisters: beautiful Meg, tomboyish Jo, delicate Beth, and Amy, the ...
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Think and Grow Rich
Greg Habstritt & Napoleon HillThink and Grow Rich is one of the most popular success book of alltime, having sold more than 60 million copies since it was first published more than 70...
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Hard Love
Peyton BanksHe was football royalty. Legendary quarterback. A champion.  Reiner Strickland had led his team to three national championships and playing a knight in shining armor was a...
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Pride and Prejudice
Jane AustenAn Apple Books Classic edition. Jane Austen’s beloved classic opens with this witty and very memorable line: “It is a truth universally acknowledged, that a single man in possessio...
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Hot Off the Press
Lexy Timms"This is what really happened… reported by a free press, for a free people…" Wes Shaw leads a secret double life. As the secret owner of a billion dollar newspap...
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Teased by Fire
Molly O'HareFrom USA Today bestselling author Molly O’Hare comes an enemiestolovers, older brother’s best friend, romantic comedy with a curvy, antisocial, supernaturalobsessed, allyearround h...
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Always Yours
Claire RayeSome things are just meant to be... Ellen Somerville and Will McIntyre met by accident and under unusual circumstances. Getting sprayed by a skunk in a parking lot wouldn’t normall...
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Finding Cinderella
Colleen Hoover#1 New York Times bestselling author of It Starts with Us and It Ends With Us writes a free novella about the search for happily ever after. A chance encounter in the dark leads ei...
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The Adventures of Sherlock Holmes
Arthur Conan DoyleAn Apple Books Classic You get not one, not two, but 25 gripping mysteries in Arthur Conan Doyle’s first of five collections of Sherlock Holmes short stories. Follow the brilliant ...
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Escape, A New Life
David J AntocciTo save herself, she had to lose everything. Trapped in a tropical paradise with no memory of how she got there, Abby is thrust into a fight for her life. Hunted by a madman, and c...
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Man In The Water
Jon HillAn attempted murder. A missing spouse. And an international conspiracy that could change the world. Jack Green has always been skeptical of socalled facts. Though he's forced ...
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All Fired Up
Kathryn ShayCaptain Jarek Zenko, a war veteran and firefighter, meets Lacey Roth at a bar one night. They don’t share their real identities, even when they retreat to a hotel. When they meet t...
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Assisting the Bosshole
Kristin MacQueenNo hot water? Check Missed the train? Check Broke my heel? Check Dropped my coffee? Check My first day of my new job can’t possibly go worse, right? Wrong. When I meet Parker Scott...
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The Odyssey
HomerAn Apple Books Classic edition. Homer’s eighthcentury epic poem is a companion to The Iliad . It tells the story of Odysseus, who journeys by ship for 10 years after the Trojan War...
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The Wonderful Wizard of Oz
L. Frank BaumAn Apple Books Classic edition. You’ve seen the iconic 1939 movie, but do you know about the talking field mice, the Winkies, and the Witch of the North that appear in the original...
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Alpha
Sybil BartelBillionaire. Mercenary. Navy SEAL. The Teams trained me to be a killer. War taught me to be ruthless. Then an illfated mission proved I was human. Combat wounded, cut loose by the ...
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Law of Attraction
Jordan HollisHow to Finally Overcome the Hurdles of Manifesting Proven, effective and enjoyable ways to help you manifest faster… Right now, think of something that makes you successful. If you...
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Tempting the King
Jessa YorkAn escaped Mafia Queen, hiding from her past. A Mafia King who wants to claim her… Giselle They think I'm lostbut I know better. I can never be found. The path I've creat...
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Teach Me
Cassandra DeanFrom awardwinning author Cassandra Dean comes a tale where lessons of pleasure between a curious, sunshine widow and a dissolute, grumpy earl leads to passion and allconsuming love...
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His Own Heaven
Jennie KewWinner of the 2021 Passionate Plume Award for BDSM Romance Finalist in the 2021 Stiletto Contest for Contemporary Romance He taught her to trust, she taught him to love. Lucy Bar...
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Whiskey Girl
Melissa BelleThey'll do anything for each other…except commit. Logan Wild isn’t just the hottest broncriding cowboy in Texas. He’s also my best friendwith benefits. And that’s all we’ll ev...
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The Count of Monte Cristo
Alexandre DumasAn Apple Books Classic edition. Alexandre Dumas’ classic paints a portrait of Edmond Dantès, a dark and calculating man who is willing to wait years to exact his perfect plan for r...
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Rogue Alpha
Kimber WhiteOne touch made her crave him. But the pull of fate could be the path to ruin. College student Laura Prince lands a plum internship deep in the Michigan wilderness. When she discove...
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The Great Gatsby
F. Scott FitzgeraldAn Apple Books Classics edition. The Roaring Twenties are in full effect in F. Scott Fitzgerald’s riveting classic. Manabouttown Jay Gatsby seems to have it all, including loads of...
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Eternal
W.J. MayShe will fight for what is hers. When the king is murdered, Katerina, his only daughter, must flee for her life. She finds herself on a strange and dangerous path. Alone for the fi...
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Silenced Girls
Roger Stelljes“ Wow wow wow!  Grips you in a choke hold and  does not let go … Oozes suspense and  bonechilling twists and turns .  Astonishing … One of those...
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Silver Santa
Lacey SilksTrapped together on Christmas, their unintended onenight stand becomes a lifechanging encounter amidst the snow. Laura Young's professional role as a security guard at the Sil...
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Peace on Earth
Maia RossCrime never takes a holiday. Why should Irma? Irma Abercrombie is an energetic retiree with a shadowy past, a mean right hook, and a profound love of Christmas. Surrounded by seaso...
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Bewitching a Highlander
Roma CordonDefying all for the love of a bewitching lass. Breena MacRae, a healer from Skye with a touch of witchery in her blood, embarks on a dangerous search for her missing father. She ar...
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Christmas in Sweetbriar Cove
Melody GraceCelebrate the holidays in Sweetbriar Cove with this festive romance collection, containing two sizzling smalltown holiday stories perfect for fans of Tessa Bailey, Sophie Kinsella...
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Dark Psychology and Manipulation
Margaret MorrisonTHE MENTAL MANIPULATOR WILL NO LONGER KEEP SECRETS FROM YOU! Are you fed up with the wool being pulled over your eyes?Are you prepared to stand up to those who believe they can man...
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Awaken Me
Jenna JacobHe was more than a ghost haunting my dreams…he was real. By day, I’m Julianna Garrett …a prim, proper accountant. By night, I’m tormented by dreams of an alpha, ambereyed Adonis wh...
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Wuthering Heights
Emily BrontëAn Apple Books Classic edition. If you’ve only ever seen Wuthering Heights on screen, you may have an image of Catherine and Heathcliff as the ultimate starcrossed lovers. But that...
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His Girl Next Door
Khardine GrayFrom USA Today Bestselling author Khardine Gray comes a sizzling hot single dad romance you won't want to miss. No strings attached fun with the ubergorgeous single d...
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School of Potential
W.J. MayUSA Today Bestselling author, W.J. May brings you a continuation of the international bestselling series, The Chronicles of Kerrigan! Come back and enjoy the famous characters, or ...
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Become A Better Version of Yourself
Ben LeightonThis ebook contains golden nuggets on how to motivate, inspire and improve your current situation. It encompasses the holistic view of self improvement from mental& emotion...
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You Are Kind
Michael GordonA little kindness goes a long way. How can you help encourage your kids to be kind from a young age? Teach kindness to preschoolers Acts of kindness can be fun, easy, and make a ...
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Just Me
Lexy TimmsWe all need somewhere where we feel safe… After leaving her abusive husband, Katherine Marshall is out on her own for the first time. She's hopped from city to city to avoid t...
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Dream Psychology
Sigmund FreudAn Apple Books Classic edition. Written by the founding father of psychoanalysis, Sigmund Freud’s 1899 book is the definitive text on learning to interpret dreams. Freud’s groundbr...
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The Art of War
Sun TzuAn Apple Books Classic edition. It’s believed that Sun Tzu wrote this Chinese military primer during the 5th century BChundreds of years before the Bible. The book’s 13 chapters ex...
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Noxious
Lexy TimmsStop setting yourself on fire to keep someone else warm. Brady and Levi have been together since high school, since before he became famous and started thinking only about himself....
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Holy Bible
The Church of Jesus Christ of Latter-day SaintsThe 2013 edition of the Holy Bible contains all of the study aids contained in the 1979 edition and includes revisions to the study aids, several new photos, updated maps, and adju...
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Inception of Gold
Lexy TimmsThings are not as bad as they seem. They are worse. Being the personal assistant to a narcissistic actress who just happens to own the key to my family's undoing isn't ex...