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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Major Genetic Syndromes

Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP) continued...

In the same study, female MSH6 mutation carriers had a cumulative risk of other Lynch cancers (i.e., ovarian, stomach, small intestine, kidney, ureter, or brain) of 11% (95% CI, 6%–19%) by age 70 years and 22% (95% CI, 12%–38%) by age 80 years.[213] The risk of LS cancers, excluding colorectal and endometrial cancers, was six times that of the general population (HR, 6.0; 95% CI, 3.4–10.7; P < .001). Male MSH6 mutation carriers showed no evidence of an increased risk of these cancers (HR, 0.8; 95% CI, 0.1–8.8; P = .9). The authors estimated that 24% (95% CI, 16%–37%) of men and 40% (95% CI, 32%–52%) of women harboring deleterious MSH6 mutations would be diagnosed with any LS cancer by age 70 years and that these values will increase to 47% (95% CI, 2%– 66%) of men and 65% (95% CI, 53%–78%) of women by age 80 years.

Practices and pitfalls in testing

One study reported that of 42 population-based probands harboring deleterious MSH6 germline mutations who were ascertained independent of their family cancer history, 30 (71%) had a family cancer history that did not meet the Amsterdam II criteria.[213]

MSH6 colorectal tumors can be MSI-high, MSI-low, or MSS. This pitfall illustrates the utility of IHC for the MMR protein expression. Eighteen of 21 (86%) of the colorectal tumors showed an MSI-high phenotype. Of the 16 endometrial tumors tested, 11 were MSI-high (69%); four were MSI-low (25%), and one was microsatellite stable (6%).[260]

In endometrial cancers with germline MSH2 mutations, loss of MSH6 frequently occurs with loss of MSH2.[299,305]



The prevalence of PMS2 germline mutations has been underappreciated for many reasons. It is the most recent of the major genes to be identified, probably has the lowest prevalence, was not felt to be worthy of serious investigation, and commercial testing is not widely available.[306,307,308] One registry study reported an incidence of 2.2% for PMS2 mutations in 184 patients with suspected LS.[309] A population-based study reported a prevalence of approximately 5% (1 of 18).[207]

Genotype-phenotype correlations

A meta-analysis of three population-based studies and one clinic-based study estimated that for carriers of PMS2 mutations, the risk of CRC to age 70 years was 20% among men and 15% among women, and the risk of endometrial cancer was 15%.[211]

In one study, patients with PMS2 mutations presented with CRC 7 to 8 years later than did those with MLH1 and MSH2 mutations. However, these families were small and did not fulfill Amsterdam criteria.[309]

Diagnostic strategies for all individuals diagnosed with CRC (universal testing)

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP), a project developed by the Office of Public Health Genomics at the Centers for Disease Control and Prevention, formed a working group to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice. The Working Group was commissioned to address the following question: Do risk assessment and MMR gene mutation testing in individuals with newly diagnosed CRC lead to improved outcomes for the patient or relatives, or are they useful in medical, personal, or public health decision-making?[310,311] The Working Group constructed economic models to assist in analyzing available evidence on clinical utility in estimating how various testing strategies might function in practice. These included mutation frequency, sensitivity and specificity of both IHC and MSI testing, and the cost of these tests. The performance of these tests is based on the risk of positivity of carrying a mutation including family history, age at diagnosis, and extracolonic cancers. In 2009, the Working Group reported that there was sufficient evidence to recommend offering genetic testing for LS to individuals with newly diagnosed CRC to reduce morbidity and mortality in relatives. They concluded that there was insufficient evidence to recommend a specific gene-testing strategy among the following four strategies tested:[310,311]

  1. All individuals with CRC tested for germline mutations in MSH2, MLH1, and MSH6. The average cost per LS detected was estimated to be $111,825.
  2. All tumors tested for MSI, followed by germline mutation analysis of MSH2, MLH1, and MSH6 offered to those with MSI-H tumors. The average cost per LS detected was estimated to be $47,268.
  3. All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2, followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. The average cost per LS detected was estimated to be $21,315.
  4. All tumors tested for absence of protein expression of MSH2, MLH1, MSH6, and PMS2 followed by targeted germline mutation analysis of MSH2, MLH1, or MSH6 offered depending on which protein was absent. If there was absence of MLH1, testing was offered for BRAF mutation–negative tumors. The average cost per LS detected was estimated to be $18,863.[311]

WebMD Public Information from the National Cancer Institute

Last Updated: February 25, 2014
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