Overlapping or Close variants in the same patients

[Amira Kotb Abdallah]

Dear all,

I would like to check what is the correct format for reporting close or overlapping variants in the same patient. And, should I exclude one variant from each pair, or both should be reported as 2 different alleles?

For example :

1)  NM_005921.1:c.2840del & NM_005921.1:c.2843_2844del (coding for 2 consequent amino acids)

2) NM_170695.3:c.25del & NM_170695.3:c.246_247del (both are coding for the same AA & cause termination).

Sincerely,

Amira 

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[Johan den Dunnen]

Dear Amira,

assuming the variants are on the same allele, the answer to your question is in proposal SVD-WG010 (not officially approved, but likely to get accepted with minor modifications), see https://hgvs-nomenclature.org/stable/consultation/SVD-WG010/. Since on DNA level the two variants are not "separated by fewer than two intervening nucleotides", variant 1 is described as NM_005921.1:c.[2840del;2843_2844del]. The predicted consequence on protein level, where the two affected residues are "separated by fewer than two intervening residues", the variant is described as p.(Thr947_Thr948delinsLys).

For variant 2 we then get to NM_170695.3:c.[25del;246_247del] with as predicted consequences p.(Ser9_Cys79delinsLeuProGlyTrpAlaProArgIleValArgAlaProAlaGlyAlaAlaLeuIleProPheHisGlyProProProThrProGlyIleProSerAlaProPheProArgLeuPheTrpArgProProAspSerProAlaAlaLeuTrpProThrPheProGlnArgArgGlyProProTrpArgProProLeuArgSerTrpGlyProPro) or p.(Ser9_Cys79delinsX[70]). Please note that the description p.[(Ser9LeufsTer125);(Pro83SerfsTer60)] would not be correct since the predicted frame shift from the 1-nucleotide deletion gets, before a stop codon is reached, "back in-frame" by the second 2-nucleotide deletion.

Please also note that SVD-WG010 gives you also the option to describe the first variant as NM_005921.1:c.[2840_2843delinsA] (see "Data providers may report adjacent variants independently and may merge nearby (non-adjacent) variants if they believe that those forms are more suitable for their data").

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op zondag 24 november 2024 om 10:48:22 UTC+1 schreef amir...@kasralainy.edu.eg: