Note: EMQN would like to acknowledge the UKNEQAS for molecular genetics which first formulated a policy for their scheme in 2005.
Over the past years the EMQN have reported wide disparities in the naming of DNA sequence variants. In 2005, for example, we saw one particular BRCA2 mutation reported in four different formats. This inconsistency is unacceptable and leads to confusion both in the laboratory and the clinical setting. To avoid confusion and clinical errors it is important that diagnostic laboratories lead the way in adopting a consistent approach to naming mutations.
Nomenclature guidelines are available from the Human Genome Variation Society (HGVS), the international body for defining gene variation nomenclature under the umbrella of the Human Genome Organization (HUGO) and the International Federation of Human Genetics Societies (IFHGS). It is therefore appropriate that we should follow these guidelines and the EMQN recommends that all labs use them (website:- http://www.hgvs.org/). However we do recognise that there remain some difficulties with the interpretation of these guidelines.
The HGVS recommend the use of a coding reference sequence wherever possible and that the A of the translation initiation codon ATG is designated base 1. One problem lies in the fact that mutations in some genes are routinely named from base 1 of a cDNA reference sequence (e.g. BRCA2 gene mutations in the BIC database using accession number U43746.1 where the A of the ATG codon is at position 229). We see that some laboratories use the numbering system according to the annotations in the cDNA reference sequence, whilst other labs quote the same reference sequence but subtract the appropriate number of untranslated nucleotides (228 in the above BRCA2 example) in order to name a mutation.
HGVS guidelines recommend the use of the ‘RefSeq’ database reference sequence but do not specify which one. We do recognise that different ‘RefSeq’ sequences for the same gene may vary. We have produced the following notes to assist in the interpretation of the nomenclature guidelines. Please let us know of any difficulties in applying them. Feedback from you will help us establish consensus recommendations.
1. Follow the HGVS guidelines and number bases starting with the A of the ATG initiation codon as base 1.
2. Use the same reference sequence as you have used in the past. However where a reference sequence does not start at the ATG different numbers must be assigned to the nucleotides to comply with the point 1.
3. Any different numbering system to that used in the reference sequence, must be noted on your report (for example; state that the numbering system starts with nucleotide 1 being the A of the ATG translational initiation codon).
4. If application of the HGVS guidelines results in a different nomenclature from that used in the past, then you should quote both old and new nomenclatures to avoid confusion with previous reports of the same mutation.
5. Always quote the reference sequence AND the version number as sequences may change from version to version.
6. In a disease such as cystic fibrosis laboratory reports frequently list the panel of mutations tested. In order to avoid a lengthy list of both old and HGVS compliant nomenclature, only mutations identified in the consultand or family need to be quoted using HGVS nomenclature.
7. Where the information is available all genetic variants must be described at both the DNA and the protein level. If the protein prediction is theoretical, this should be clearly written on the lab report.
8. If the testing method used does not unambiguously identify a specific base change, the nomenclature used should reflect this.
9. It is recognised that some recurrent mutations come by historical names which do not comply at all with the HGVS recommendations (e.g. ‘DeltaF508’ in the CFTR gene or ‘Factor V Leiden mutation’ in the FV gene). It appears unrealistic that the use of such trivial names in the clinical context will ever be replaced by systematic nomenclature. Therefore, it is recommended that HGVS nomenclature is used in addition to the trivial name when appropriate.
