Compound heterozygosity for two MSH2 mutations suggests mild consequences of the initiation codon variant c.1A>G of MSH2

Abstract

Mono-allelic germline mutations in mismatch repair (MMR) genes lead to Lynch syndrome, an autosomal dominant syndrome with an increased risk of predominantly colorectal and endometrial cancers. Bi-allelic germline mutations in MMR genes predispose to haematological malignancies, brain tumours, gastrointestinal tumours, polyposis and features of neurofibromatosis type 1 in early childhood. We report a brother and a sister with bi-allelic germline mutations in MSH2; a pathogenic deletion of the first 6 exons and a variant of the initiation codon (c.1A4G (p.Met1?)), whereas their phenotypes (four colorectal cancers, small bowel carcinoma and 15 adenomas at age 39 and 48, and colorectal cancer, endometrial cancer and four adenomas at age 33 and 44, respectively) are more suggestive of a mono-allelic pathogenic MMR gene mutation. The carcinomas showed microsatellite instability in the presence of MLH1, PMS2, MSH2 and MSH6 proteins, indicating that the variant c.1A4G leads to an alternative protein with reduced activity that is retained in the tumours. Our data suggest that the MSH2 variant c.1A4G (p.Met1?) should not be considered as a regular pathogenic mutation that leads to a strongly increased cancer risk, though it possibly contributes to a more severe phenotype when combined with a truncating mutation on the other allele.

Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘Care for CMMRD’ (C4CMMRD)

“…This may be partly due to the fact that the group of MLH1 / MSH2 biallelics contains two siblings compound heterozygous for the hypomorphic MSH2 mutation c.1A>G and a deletion encompassing exons 1–6 of this gene (c.1-?_1076+?del). These patients developed multiple LS-associated tumours in their fourth and fifth decades of life 19. Excluding these two siblings, the differences between the genetic groups are more obvious (5 vs 8 and 10 years).…”

“…The remaining four patients had colorectal adenomas when they were young adults. Only four patients were older than 25 years when they were diagnosed with their first tumour; in all four cases a CRC 13 19 41. These four patients carried at least one allele a likely hypomorphic MSH2 , MSH6 and PMS2 mutation, respectively, and, therefore, may genetically as well as clinically represent an intermediate phenotype between CMMRD and LS.…”

“…More than 60% (91/146) of the CMMRD patients were reported to show at least one CALM or hyperpigmented skin area (table 4) and only four published19 30–32 and one so far unpublished patient have been explicitly reported to lack these pigmentary alterations. The vast majority of these patients had multiple (two or more) CALMs, but they did not always reach the critical number of ≥6, which is needed to be a diagnostic criteria of NF1.…”

Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations

“…First, initiation codon variants such as c.3G4A identified in this study, have been widely suggested to be a disease causing mutations. 19 Second, small in frame deletions usually cause protein misfolding and instability and this suggested that they will be disease causing mutations. 20 The c.169_171del (p.V57del) mutation identified in this study might also lead to protein misfolding, because it is located between two conserved amino acids, one branched (valine) and one polar (threonine).…”

Clinical relevance of rare germline sequence variants in cancer genes: evolution and application of classification models

“…It is also likely that analysis of considerably large datasets will be required to better define the presentation phenotype of co-occurring mutations, especially for compound heterozygosity of two variants in the same gene that are associated with only moderately reduced function. Indeed, there is evidence that some compound heterozygote mutation carriers have considerably milder phenotype than others [20,21]. The issue of co-occurrence may be further complicated by the formation of heterodimer complexes between the different MMR proteins.…”