Background

Genetic testing is conducted for diverse purposes, including confirmation of diagnosis, risk prediction, carrier testing and reproductive decision-making. The identification of germ-line mutations in patients with inherited cancer syndromes enables them to be included in cancer surveillance programmes. Such programmes are effective in reducing cancer mortality in the families concerned. Moreover, family members who do not carry the mutation can be treated safely as low-risk individuals, avoiding unnecessary screening and preventing anxiety in the individuals concerned. Unfortunately, the number of suspected familial cancer cases in which a causative mutation is identified is far from ideal. All members from a family with a strong history of cancer and no causative mutation detected are included in a surveillance program. Identification of mutations depends on the specific syndrome and the criteria applied to select patients for genetic analyses.

The results of sequence-based genetic tests may be reported to physicians as: 1) positive, in which a mutation that clearly disrupts gene function is detected and is highly likely to have clinical consequences; 2) a genetic variant is detected but it is not known whether the variant has any effect on gene function that might confer an increased cancer risk (these variants are known as variants of uncertain/unclassified significance or unclassified variants [UVs]); and 3) negative, in which deleterious variant or UV is detected [1].

The majority of UVs are missense mutations or small in-frame deletions. The human gene pool harbours a vast number of rare missense substitutions, 70% of which are at least mildly deleterious [2]. Integration of various lines of evidence may help to classify UVs. Information on: 1) frequencies in cases and controls, 2) co-occurrence (in trans) with deleterious mutations, 3) co-segregation with disease in pedigrees, 4) pathological factors, 5) amino acid polarity or size, 6) evolutionary conservation of the residue, 7) splice predictions and 8) in vitro and/or in vivo functional assays may enable UVs to be classified as pathogenic or non-pathogenic [3].

Lynch syndrome (MIM# 120435) (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset colorectal cancer (CRC), cancer of the endometrium and tumours of the stomach, pancreas, small intestine, ovary, bladder and bile duct [4]. LS-associated tumours are characterized by DNA mismatch repair (MMR) deficiency, which may be evidenced by microsatellite instability (MSI) or loss of expression of MMR proteins using immunohistochemistry [5]. The proportion of genetic UVs in LS varies from 1/5 to 1/3 of all unique variants detected [6].

