DNA strand intertwining with a family tree, symbolizing genetics and inheritance in Lynch syndrome.

Decoding Lynch Syndrome: A Young Patient's Genetic Puzzle and What It Means for You

Rhea Morgan in Health & Wellness December 2025 • 5 min read.

"Discover a novel MLH1 gene variant linked to Lynch syndrome in a young Japanese patient, highlighting the importance of genetic testing and personalized surveillance for those at risk."

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited condition that significantly increases the risk of developing certain cancers, most notably colorectal cancer. It's caused by mutations in genes responsible for DNA mismatch repair (MMR), which act as proofreaders during cell division. When these genes are faulty, errors accumulate, leading to cancer development. Lynch syndrome accounts for an estimated 2-4% of all colorectal cancer cases, making it a significant concern for individuals with a family history of the disease.

While colorectal cancer is the most common manifestation, Lynch syndrome also elevates the risk of endometrial, gastric, ovarian, and other cancers. This broader cancer spectrum is particularly relevant for individuals of Asian descent, who have a higher propensity for developing gastric cancer within the context of Lynch syndrome. Understanding the intricacies of this syndrome, including its varied presentation and genetic underpinnings, is crucial for accurate diagnosis and personalized management.

Genetic testing plays a pivotal role in identifying individuals with Lynch syndrome. As our knowledge of MMR gene variants expands, so does our ability to diagnose and manage this condition effectively. In this article, we delve into a compelling case study of a young Japanese patient diagnosed with Lynch syndrome due to a novel germline variant in the MLH1 gene. This case underscores the importance of genetic screening, early detection, and tailored surveillance strategies for individuals and families affected by Lynch syndrome.

The Case: Uncovering a Novel MLH1 Variant

DNA strand intertwining with a family tree, symbolizing genetics and inheritance in Lynch syndrome.

At 32 years old, the patient, of Japanese descent, presented for genetic counseling after undergoing multiple surgeries for colon cancer. His medical journey began at age 29 when he was diagnosed with advanced rectal cancer, necessitating robot-assisted laparoscopic intersphincteric resection. Histological examination of the resected tumor revealed adenocarcinoma invading beyond the muscularis propria, the outer layer of the rectum. This aggressive presentation at a young age raised suspicion for an underlying genetic predisposition.

Subsequent surveillance revealed a non-granular, laterally spreading tumor (LST-NG) in the ascending colon. This second tumor, removed via endoscopic submucosal dissection (ESD), showed submucosal invasion and lymph duct permeation. Further complicating the picture, the first tumor exhibited mucinous carcinoma features, while the second displayed moderate to poor differentiation. This combination of early-onset, multiple colorectal cancers with distinct histological characteristics strongly suggested Lynch syndrome.

Family History: The patient's paternal aunt had breast cancer, and his paternal grandfather had gastric cancer diagnosed at age 40.
Bethesda Guidelines: The patient met the revised Bethesda guidelines, prompting further evaluation.
Microsatellite Instability (MSI) Testing: Analysis revealed a high frequency of MSI (5 out of 5 markers), indicating impaired DNA mismatch repair.
Immunohistochemistry (IHC): IHC of MMR proteins showed a loss of MLH1 and PMS2 expression in the rectal cancer tissue.

Following informed consent, germline DNA analysis was performed. Whole-exome sequencing (WES) revealed a novel heterozygous mutation in the splice donor site of MLH1 intron 6, designated NM_000249.3:c.545+2T>C (IVS6+2T>C). This specific alteration, located at Chr3:37050398 (GRCh37), had not been previously reported in databases like ClinVar, HGMD, or ExAC. While a different sequence variant at this locus (MLH1 c.545+2T>A) was previously identified as disease-causing, the novelty of the identified mutation in the Japanese patient warranted further investigation.

Implications and the Path Forward

The discovery of this novel MLH1 germline variant (IVS6+2T>C) provides critical insight into the molecular mechanisms driving Lynch syndrome. Functional analysis confirmed that this mutation causes abnormal splicing of MLH1 mRNA, leading to a dysfunctional protein and, consequently, impaired DNA mismatch repair. This case highlights the importance of considering intronic variants in genetic testing for Lynch syndrome, particularly in patients presenting with early-onset colorectal cancer and suggestive family histories.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1038/s41439-018-0002-1, Alternate LINK

Title: A Novel Mlh1 Intronic Variant In A Young Japanese Patient With Lynch Syndrome

Subject: Genetics

Journal: Human Genome Variation

Publisher: Springer Science and Business Media LLC

Authors: Yoshimi Kiyozumi, Hiroyuki Matsubayashi, Yasue Horiuchi, Takuma Oishi, Masato Abe, Sumiko Ohnami, Akane Naruoka, Masatoshi Kusuhara, Ken Yamaguchi

Published: 2018-04-23

Everything You Need To Know

What is Lynch syndrome, and why is it important to understand?

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited condition that significantly elevates the risk of developing various cancers, most notably colorectal cancer, but also endometrial, gastric, and ovarian cancers. Understanding Lynch syndrome is crucial because it allows for early detection through genetic testing, personalized cancer surveillance, and proactive health management, potentially saving lives, especially for individuals with a family history of related cancers. It's caused by mutations in genes responsible for DNA mismatch repair (MMR). When these genes are faulty, errors accumulate, leading to cancer development. This accounts for an estimated 2-4% of all colorectal cancer cases. Identifying it allows for targeted screening and preventative measures to be taken.

How does a mutation in the MLH1 gene contribute to the development of Lynch syndrome, as seen in the young Japanese patient?

A mutation in the MLH1 gene, one of the key DNA mismatch repair (MMR) genes, disrupts the normal function of the MMR system. In the case of the young Japanese patient, a novel germline variant (IVS6+2T>C) in MLH1 was discovered. Functional analysis revealed that this specific mutation causes abnormal splicing of MLH1 mRNA, leading to a dysfunctional MLH1 protein. Since MLH1 is crucial for repairing errors during DNA replication, its dysfunction leads to the accumulation of mutations and an increased risk of cancer development, which is characteristic of Lynch syndrome. The loss of MLH1 expression, along with PMS2, was observed via Immunohistochemistry (IHC) testing of the rectal cancer tissue.

What role does genetic testing play in diagnosing Lynch syndrome, and what are the implications of identifying a novel genetic variant like the one found in the Japanese patient?

Genetic testing is crucial for diagnosing Lynch syndrome because it identifies mutations in DNA mismatch repair (MMR) genes, such as MLH1, MSH2, MSH6, and PMS2. Identifying a novel genetic variant, like the IVS6+2T>C mutation in MLH1 found in the Japanese patient, expands our understanding of the genetic basis of Lynch syndrome. This discovery confirms the importance of including intronic variants in genetic screening, particularly in patients with early-onset colorectal cancer and a relevant family history. It also highlights the need for continuous updating of genetic databases (like ClinVar, HGMD, and ExAC) and the need for functional analysis to confirm the pathogenicity of these novel variants. Furthermore, it supports the development of personalized surveillance strategies for those carrying such variants.

Beyond colorectal cancer, what other types of cancers are associated with Lynch syndrome, and why is this broader cancer spectrum important for individuals of Asian descent?

Besides colorectal cancer, Lynch syndrome increases the risk of endometrial, gastric, ovarian, and other cancers. This broader cancer spectrum is particularly relevant for individuals of Asian descent because they have a higher propensity for developing gastric cancer within the context of Lynch syndrome. Therefore, comprehensive screening and surveillance strategies that include monitoring for these other cancers are essential for managing Lynch syndrome in this population. For example, the patient's paternal grandfather had gastric cancer diagnosed at age 40.

How did the patient's case, including the multiple surgeries and family history, contribute to the suspicion and diagnosis of Lynch syndrome, and what guidelines were used?

The patient's case presented several red flags that raised suspicion for Lynch syndrome. These included the early-onset of advanced rectal cancer at age 29, the subsequent development of a second tumor in the ascending colon, and distinct histological features of both tumors (mucinous carcinoma in the first and moderate to poor differentiation in the second). The family history of cancer, specifically breast cancer in the patient's paternal aunt and gastric cancer in his paternal grandfather, further strengthened the suspicion. The patient met the revised Bethesda guidelines, which prompted further evaluation. Microsatellite Instability (MSI) testing showed a high frequency of MSI (5 out of 5 markers), and Immunohistochemistry (IHC) revealed a loss of MLH1 and PMS2 expression, ultimately leading to germline DNA analysis and the identification of the novel MLH1 mutation, confirming the diagnosis of Lynch syndrome.