Correction: Identification of Novel Pathogenic Sequence Variants of the Mismatch Repair Genes During Screening for Lynch Syndrome in a Single Centre of Eastern Hungary

Correction: Journal of Gastrointestinal Cancer

10.1007/s12029-020-00359-2

The original version of this article unfortunately contained a mistake. The variants listed in Table 3 of the original version of this article are not in line with the latest HGVS (Human Genome Variation Society) nomenclature (version 19.01).

Table 3.

The locations of the variants and the 2 hMLH1 promoter hypermethylation

	Sex	Age at diagnosis	Amsterdam II	Bethesda	MSI	MLH1 promoter hyper-methylation	Affected gene	Type of the variant	Variant*	Effect on protein level*
1	F	44	No	yes	H	no	MLH1	Probably Founder	c.143A>C	p.Q48P
2	M	40	No	yes	H	no	MLH1	New mutation	c.901dup	p.Q301Pfs*6
3	M	43	No	yes	H	no	MSH2	Probably Founder	c.2038C>T	p.R680*
4	M	32	Yes	no	H	no	EPCAM	Large deletion	g.(47601138_47612316)_(47617251_47627529)del	Uncertain
5	M	43	No	yes	H	yes		No mutation hyper-methylation	–
6	F	30	Yes	no	H	yes	MSH2	New mutation with hyper-methylation	c.[2366_2367del;2370_2375del] or c.2366_2375delinsTT	p.A789Vfs*7

^*NCBI RefSeq accession numbers: NM_000249.4 for MLH1 and NM_000251.3 for MSH2 and NC_000002.12 for EPCAM

The correct variants are listed in the corrected Table 3 below.

The relevant corrected sections:

Mutations Identified in the hMLH1 Gene

A pathogenic sequence variant of hMLH1 gene was found in 2 patients (Table 3). In patient #1, a missense mutation in codon 48, exon 2 (c.143A>C) was identified. This mutation results in an amino acid change: from glutamine to proline (p.Q48P). We have previously published this mutation as it was found in our several screened families [26, 27]. It has also been reported by others as a pathogenic sequence variant of the MMR genes causing Lynch syndrome [30], and can be found in multiple databases, such as ClinVar, dbSNP, and OMIMdatabases (https://www.ncbi.nlm.nih.gov/clinvar/variation/89739, https://www.ncbi.nlm.nih.gov/snp/587778914). Based on these circumstances, we suspect that this is a European founder mutation. During the DNA sequencing of the second patient, an ins>frameshift>STOP mutation of the exon 11 of hMLH1 gene was identified. This is a one-nucleotide insertion which causes a frameshift when an extra cytosine is inserted into the 901 position. During translation, a proline will be inserted instead of glutamine at the 301 position, and behind 4 more amino acids there will be a STOP codon. Altogether, 5 new amino acids will be expressed and then the translation will be stopped (P-X-X-X-X-STOP). This mutation cannot be found in any of the databases and was not published yet by other groups. We believe that it is a new pathogenic sequence variant of the MMR genes, which is responsible for the development of Lynch syndrome in this patient.

Mutations Identified in the hMSH2 Gene

MSI-H status and absence of nuclear expression of the hMSH2 and hMSH6 proteins were found in the third patient’s tumor in Table 3. DNA sequencing revealed a pathogenic nonsense mutation in exon 13 at codon 680 in the hMSH2 gene. An arginine to STOP codon change was caused by this mutation, which results in a cytosine-thymine change at 2038 position, thus leading to premature protein chain termination. It is a well-known pathogenic sequence variant of the MMR genes causing Lynch syndrome and has been reported several times in the literature. It can also be found in dbSNP and ClinVar databases (https://www.ncbi.nlm.nih.gov/snp/ 63749932, https://www.ncbi.nlm.nih.gov/clinvar/variation/ 36572/#summary-evidence). Patient #6 had a simultaneous hMLH1 promoter hypermethylation and hMSH2 gene mutation on exon 14 showing double deletion→frameshift→ STOP mutation. This mutation involves multiple nucleotide (c.[2366_2367del;2370_2375del]), which causes a frameshift. As a consequence, the frameshift starts at the 789 position in the protein, where valine is expressed instead of alanine. Five more codons then follow and the sixth is a STOP codon (V-X-X-X-X-X-STOP). Based on the ClinVar database, this region is very variable and multiple mutations have been published, most of which were associated with Lynch syndrome (https://www.ncbi.nlm.nih.gov/clinvar? term = 609309[MIM]). To the best of our knowledge, this mutation has not been published so far. We believe that this is a new pathogenic sequence variant from an unstable region in the hMSH2 gene associated with Lynch syndrome.