Lynch syndrome (PMS2)

Overview

Lynch syndrome is an inherited condition that increases the risk of developing several types of cancer, most commonly colorectal (bowel) cancer and endometrial (womb) cancer. It is one of the most common inherited cancer predisposition syndromes [PMID:33675087]. While cancer is common, Lynch syndrome means that an individual has a higher chance of developing these cancers, often at an earlier age, compared to the general population. It is also associated with an increased risk of developing more than one cancer during a lifetime.

Lynch syndrome is caused by changes in specific genes that are responsible for repairing errors in DNA. When these genes do not function correctly, DNA errors can accumulate, leading to uncontrolled cell growth and, eventually, cancer. Recognising Lynch syndrome is important because it allows individuals and their families to access regular screening and risk-reducing strategies.

Symptoms & clinical features

Lynch syndrome itself does not cause any specific symptoms. Instead, the condition is identified through the development of Lynch-associated cancers or by a family history suggestive of the syndrome. Cancers linked to Lynch syndrome often develop at a younger age than sporadic cancers, meaning cancers that occur by chance in the general population. For example, colorectal cancer might be diagnosed in individuals in their 40s or 50s, rather than their 60s or 70s.

The specific symptoms an individual experiences will depend on the type and location of cancer that develops. For colorectal cancer, symptoms can include changes in bowel habits, blood in the stool, abdominal pain, or unexplained weight loss. For endometrial cancer, symptoms may include unusual vaginal bleeding, especially after menopause, or pelvic pain. Other cancers associated with Lynch syndrome, such as ovarian, stomach, small bowel, urinary tract, brain, and skin cancers, will present with their own distinct symptoms.

Video: Is cancer in your genes?

Affected organs

Lynch syndrome primarily affects organs where cells divide frequently, making them more susceptible to DNA errors when repair mechanisms are faulty. The most commonly affected organs are the large intestine (colon and rectum) and the uterus (endometrium).

Other organs that can be affected include the ovaries, stomach, small intestine, urinary tract (kidneys, bladder, ureters), brain (specifically glioblastomas), and sebaceous glands in the skin (leading to certain skin tumours). While the risk of cancer in these other organs is generally lower than for colorectal or endometrial cancer, it is still elevated compared to the general population. The spectrum of cancers and the organs affected can vary between individuals, even within the same family.

Colon

Elevated colorectal cancer risk

Cellular impact

Mechanism at cellular level

Risks & severity

The severity of Lynch syndrome varies, with some individuals developing multiple cancers and others remaining cancer-free throughout their lives. PMS2-related Lynch syndrome is generally considered to have lower cancer risks (lower penetrance) compared to Lynch syndrome caused by changes in other mismatch repair genes [PMID:22009230]. However, individuals with PMS2 variants still have an increased lifetime risk of developing certain cancers.

For those with PMS2-related Lynch syndrome, the lifetime risk of colorectal cancer is estimated to be between 10-20%, which is higher than the general population risk but lower than for other Lynch syndrome genes. The lifetime risk for endometrial cancer is also increased, typically ranging from 15-20%. The average age of onset for these cancers is often younger than sporadic cancers, commonly in the 50s. Other associated cancers, such as ovarian, stomach, or urinary tract cancers, have lower but still elevated lifetime risks. Regular surveillance is key to managing these risks.

Genetic causes

Lynch syndrome is caused by inherited pathogenic variants (changes) in genes responsible for DNA mismatch repair (MMR). These genes normally act as proofreaders, correcting errors that occur when DNA is copied. When one of these genes has a pathogenic variant, the repair system doesn't work as effectively, leading to an accumulation of errors and an increased risk of cancer.

One of the genes associated with Lynch syndrome is PMS2. The PMS2 gene encodes a protein that forms part of the MMR complex. This complex is crucial for identifying and repairing small errors that happen during DNA replication. Pathogenic variants in PMS2 impair the ability of this protein to function correctly, disrupting the overall DNA repair process [PMID:24075199]. This impaired repair mechanism allows genetic errors to accumulate, which can eventually lead to cancer development. Other genes linked to Lynch syndrome include MLH1, MSH2, and MSH6.

• PMS2
  PMS1 homolog 2, mismatch repair system component
  The PMS2 gene provides instructions for a protein that is a key component of the DNA mismatch repair system, responsible for correcting errors during DNA replication.

Inheritance pattern

Lynch syndrome is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered gene from one parent to be affected by the condition. Each child of an individual with Lynch syndrome has a 50% (1 in 2) chance of inheriting the pathogenic variant. This chance is the same for every pregnancy, regardless of the sex of the child or whether other children have inherited the variant.

If a parent has Lynch syndrome, their children, siblings, and other close relatives may also be at risk of carrying the same genetic variant. Genetic testing can be offered to family members once a specific pathogenic variant has been identified in a family. This allows at-risk relatives to understand their own cancer risks and consider appropriate screening and management strategies.

Diagnosis & testing

The diagnosis of Lynch syndrome is typically suspected based on a personal or family history of specific cancers, particularly if they occur at younger ages. Tumour testing is often the first step; this involves examining cancer tissue for certain characteristics, such as microsatellite instability (MSI) or the absence of MMR proteins (including PMS2), which can indicate a faulty DNA repair system [PMID:33675087].

If tumour testing suggests Lynch syndrome, or if there is a strong family history, a referral to a clinical genetics service is made. Here, genetic testing is offered to confirm the diagnosis. This involves a blood test to look for a pathogenic variant in genes like PMS2. In the UK, genetic testing for Lynch syndrome is available through the NHS Genomic Medicine Service, often under specific R-codes such as R189 (Germline susceptibility to common solid tumours). A confirmed genetic diagnosis can then guide surveillance and management for the affected individual and allow for cascade testing of at-risk family members.

Management & lifestyle

Management for individuals diagnosed with Lynch syndrome focuses on regular cancer surveillance and risk-reducing strategies, rather than treating the underlying genetic cause. This aims to detect cancers early when they are most treatable, or to prevent them from developing. Surveillance protocols are tailored to the specific gene involved and individual risk factors.

For individuals with PMS2-related Lynch syndrome, regular colonoscopies are recommended, typically starting at a younger age and performed more frequently than for the general population, to detect and remove precancerous polyps. Women are generally offered regular gynaecological surveillance, which may include transvaginal ultrasound and endometrial biopsies, to screen for endometrial and ovarian cancers. Other screening may be considered based on family history and specific risks. Risk-reducing surgeries, such as prophylactic hysterectomy and oophorectomy, may be discussed with women after childbearing is complete. Lifestyle factors, such as maintaining a healthy weight, regular physical activity, and a balanced diet, are generally encouraged as part of overall health management, although their specific impact on cancer risk in Lynch syndrome is still an area of ongoing research. All management plans are made in consultation with specialist healthcare professionals within the NHS framework.

UK care pathway

In the UK, individuals suspected of having Lynch syndrome or those diagnosed with it are managed through the NHS Genomic Medicine Service (GMS). The pathway typically begins with a referral from a GP or specialist to a clinical genetics service. Genetic counsellors play a vital role in providing information, supporting decision-making about genetic testing, and helping families understand the implications of a diagnosis.

Genetic testing for Lynch syndrome is available through the GMS, with specific tests outlined by NHS England's National Genomic Test Directory under relevant R-codes (e.g., R189 for germline susceptibility to common solid tumours). Following a diagnosis, individuals are usually referred to specialist cancer genetics clinics where multidisciplinary teams develop personalised surveillance and management plans in line with national guidelines. This comprehensive approach ensures individuals receive consistent, high-quality care.

Related conditions

Lynch syndrome is part of a broader group of inherited conditions that increase cancer risk. It is important to distinguish Lynch syndrome from other hereditary cancer syndromes that may present with similar cancer types or family histories. For instance, Familial Adenomatous Polyposis (FAP) also significantly increases colorectal cancer risk but is characterised by the development of hundreds to thousands of polyps in the colon, a feature not typically seen in Lynch syndrome.

Another related concept is Constitutional Mismatch Repair Deficiency (CMMRD), a very rare, severe childhood cancer syndrome caused by inheriting pathogenic variants in both copies of an MMR gene (one from each parent). This leads to a much earlier onset of multiple childhood cancers, including brain tumours and haematological malignancies, and is distinct from the autosomal dominant inheritance pattern of Lynch syndrome. Understanding these distinctions is crucial for accurate diagnosis, genetic counselling, and appropriate management strategies.

Frequently asked questions