Table 1.
Examples of relevant mutations and their preferred clinical and selected inconsistent variant annotations
| Gene symbol | Amino acid alteration | Nucleotide alteration Transcript ID(gene):coding DNA position (AA change) | Genomic COORDINATES Chromosome:position(assembly) | Clinical relevance/context |
|---|---|---|---|---|
| ABL1 | T315I | NM_005157.6(ABL1):c.944C>T (p.Thr315Ile) | Chr9:130872896C>T(GRCh38)=Chr9:133748283C>T(GRCh37) |
Imatinib resistance mutation MANE selected |
| T334I (same as T314I) | NM_007313.2(ABL1):c.1001C>T (p.Thr334Ile) | Same as above | ||
| ABL1 | M351T | NM_005157.6(ABL1):c.1052T>C (p.Met351Thr) | Chr9:130873004T>C(GRCh38)=Chr9:133748391T>C(GRCh37) |
Imatinib resistance mutation MANE selected |
| M370T (same as M351T) | NM_007313.2(ABL1):c.1109T>C (p.Met370Thr) | Same as above | ||
| ABL1 | E236K | NM_005157.6(ABL1):c.706G>A (p.Glu236Lys) | Chr9:130862919G>A(GRCh38)=Chr9:133738306G>A(GRCh37) |
Imatinib resistance mutation MANE selected |
| E255K (same as E236K) | NM_007313.2(ABL1):c.763G>A (p.Gly255Lys) | Same as above | Imatinib resistance mutation | |
| BRAF | V640E* | NM_001374258.1(BRAF):c.1919T>A (p.Val640Glu) | Chr7:140753336T>A(GRCh38)=Chr7:140453136T>A(GRCh37) |
Targetable BRAF mutation MANE selected |
| V600E | NM_001378468.1(BRAF):c.1799T>A (p.Val600Glu) | Same as above | Targetable BRAF mutation | |
| V599E (same as V600E) | NM_001378468.1(BRAF):c.1799T>A (p.Val599Glu) | Same as above | Initial numeration was disregarding the first methionine; not in use anymore | |
| EGFR | A289T | NM_005228.5(EGFR):c.865G>A (p.Ala289Thr) | Chr7:55221821G>A(GRCh37)=Chr7:55154128G>A(GRCH38) | Hotspot variant (used in COSMIC) |
| A244T (same as A289T) | NM_001346897.2(EGFR):c.730G>A (p.Ala244Thr) | Same as above | Hotspot variant (used in TCGA) | |
| EGFR | L858R | NM_005228.5(EGFR):c.2573T>G (p.Leu858Arg) | Chr7:55191822T>G(GRCh38)=Chr7:55259515 T>G(GRCh37) |
Targetable EGFR hotspot mutation MANE selected |
| L813R (same as L858R) | NM_001346897.2(EGFR):c.2438T>G (p.Leu813Arg) | Same as above | Targetable EGFR hotspot mutation | |
| L805R (same as L858R) | NM_001346900(EGFR):c.2414T>G (p.Leu805Arg) | Same as above | Targetable EGFR hotspot mutation | |
| L591R (same as L858R) | NM_001346941(EGFR):c.1772T>G (p.Leu591Arg) | Same as above | Targetable EGFR hotspot mutation | |
| EGFR | T790M | NM_005228.5(EGFR):c.2369C>T (p.Thr790Met) | Chr7:55181378C>T(GRCh38)=Chr7:55249071C>T(GRCh37) | EGFR resistance/targetable mutation |
| T745M (same as T790M) | NM_001346897.2(EGFR):c.2234C>T (p.Thr745Met) | Same as above | EGFR resistance/targetable mutation | |
| ERBB2 | V777L b | NM_004448.3(ERBB2):c.2329G>T (p.Val777Leu) b | Chr17:39724747(GRCh38)=Chr17:37881000(GRCh37) |
Oncogenic signaling No MANE selection |
| V777L b | NM_004448.3(ERBB2):c.2329G>C (p.Val777Leu) b | Same as above | Different nucleotide change converges at amino acid level | |
| V747L (same as V777L) | NM_001005862.2:c.2239G>T (p.Val747Leu) | Same as above | Oncogenic signaling | |
| V762L (same as V777L) | NM_001289936.1:c.2284G>T (p.Val762Leu) | Same as above | Oncogenic signaling | |
| FGFR2 | N549H | NM_00141.5(FGFR2):c.1645A>C (p.Asn549His) | Chr10:121498522A>C(GRCh38)=Chr10:123258036A>C(GRCh37) |
Crouzon syndrome MANE selected |
| N550H (same as N549H) | NM_001144913.1(FGFR2):c.1648A>C (p.Asn550His) | Same as above | Crouzon syndrome | |
| N437H (same as N549H) | NM_001144914.1(FGFR2):c.1309A>C (p.Asn437His) | Same as above | Crouzon syndrome | |
| H3(F3A) | K28M | NM_002107.6(H3F3A):c.83A>T (p.Lys28Met) | Chr1:226064434(GRCh38)=Chr1:226252135(GRCh37) | Diagnostic biomarker for midline glioma |
| K27 (same as K28) | NM_002107.6(H3F3A):c.83A>T (p.Lys27Met) | Same as above | Initial numeration was disregarding the first methionine; not in use anymore | |
| H3F3A | G35R | NM_002107.6(H3F3A):c.100G>C (p.Gly35Arg) | Chr1: 226064451G>C(GRCh38)=Chr1:226252152G>C(GRCh37) | Diagnostic biomarker for midline glioma |
| G34R (same as G35R) | NM_002107.6(H3F3A):c.100G>C (p.Gly34Arg) | Same as above | Initial numeration was disregarding the first methionine; not in use anymore | |
| MET | T992I | NM_000245.4(MET):c.2975C>T (p.Thr992Ile) | Chr7:116771936C>T(GRCh38)=Chr7:116411990C>T(GRCh37) |
SNP/activating germline variant MANE selected |
| T1010I (same as T992I) | NM_001127500.3(MET):c.3029C>T (p.Thr1010Ile) | Same as above |
Single nucleotide polymorphisms Activating germline variant |
|
| MET | D1228N | NM_000245.4(MET):c.3682G>A (Asp1228Asn) | Chr7: 116783353G>A(GRCh38)=Chr7:116423407G>A(GRCh37) |
Resistance mutation MANE selected |
| D1246N (same as D1228N) | NM_001127500.3(MET):c.3736G>A (Asp1246Asn) | Same as above | Resistance mutation |
a
BRAF V640E is currently MANE selected (https://www.ncbi.nlm.nih.gov/clinvar/variation/13961/, accessed July 7, 2021).
b
Different nucleotide changes can converge at the amino acid level.
Abbreviations: AA, amino acids; COSMIC, Catalogue of Somatic Mutations in Cancer; MANE, Matched Annotation from NCBI and EMBL‐EBI; SNP, single nucleotide polymorphism; TCGA, The Cancer Genome Atlas.