Gene Variant Detail

Gene MET
Variant D1228N
Impact List missense
Protein Effect gain of function
Gene Variant Descriptions MET D1228N lies within the protein kinase domain of the Met protein (UniProt.org). D1228N results in constitutive Met autophosphorylation and increased substrate phosphorylation, and is transforming in cell culture (PMID: 9826708), and has been associated with acquired resistance to Xalkori (crizotinib) (PMID: 28522754).
Associated Drug Resistance Y

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Transcript NM_000245
gDNA chr7:g.116783353G>A
cDNA c.3682G>A
Protein p.D1228N
Source Database RefSeq
Genome Build GRCh38/hg38
Transcript gDNA cDNA Protein Source Database Genome Build
NM_000245 chr7:g.116783353G>A c.3682G>A p.D1228N RefSeq GRCh38/hg38

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Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MET amp MET D1228N triple-receptor negative breast cancer predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, MET D1228N was identified as an acquired mutation at disease progression in a patient with triple-receptor negative breast cancer harboring a 30-fold amplification of MET, after initial response to Xalkori (crizotinib) treatment (Proceedings of the American Association for Cancer Research, Vol 60, Mar 2019, Abstract #1317). detail...
MET amp MET D1228N triple-receptor negative breast cancer predicted - sensitive Cabozantinib Case Reports/Case Series Actionable In a clinical case study, Cometriq (Cabometyx, cabozantinib) treatment resulted in stable diseases in a patient with triple-receptor negative breast cancer harboring a 30-fold amplification of MET whom developed resistance to Xalkori (crizotinib) after acquiring MET D1228N (Proceedings of the American Association for Cancer Research, Vol 60, Mar 2019, Abstract #1317). detail...
MET D1228N Advanced Solid Tumor predicted - resistant Crizotinib Preclinical Actionable In a preclinical study, transformed cells expressing mouse MET D1226N (corresponds to MET D1228N in humans) were resistant to treatment with Xalkori (crizotinib), demonstrating sustained cell growth in culture and minimal tumor growth inhibition in mouse models (PMID: 28396313). 28396313
MET D1228N Advanced Solid Tumor predicted - resistant Savolitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing mouse MET D1226N (corresponds to MET D1228N in humans) were resistant to treatment with Savolitinib (AZD6094), demonstrating sustained cell growth in culture (PMID: 28396313). 28396313
MET D1228N Advanced Solid Tumor predicted - resistant Capmatinib Preclinical Actionable In a preclinical study, transformed cells expressing mouse MET D1226N (corresponds to MET D1228N in humans) were resistant to treatment with Capmatinib (INC280), demonstrating sustained cell growth in culture and minimal tumor growth inhibition in mouse models (PMID: 28396313). 28396313
MET D1228N Advanced Solid Tumor sensitive Merestinib Preclinical - Cell culture Actionable In a preclinical study, Merestinib (LY2801653) inhibited growth of transformed cells over expressing MET D1228N in culture (PMID: 23275061). 23275061
MET D1228N Advanced Solid Tumor predicted - sensitive BMS-777607 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing mouse MET D1226N (corresponds to D1228N in humans) were sensitive to treatment with BMS-777607 (ASLAN002), demonstrating inhibition of cell growth in culture (PMID: 28396313). 28396313
MET D1228N Advanced Solid Tumor predicted - sensitive Cabozantinib Preclinical Actionable In a preclinical study, transformed cells expressing mouse MET D1226N (corresponds to MET D1228N in humans) were sensitive to treatment with Cometriq (Cabometyx, cabozantinib), demonstrating inhibition of cell growth in culture and tumor growth inhibition in mouse models (PMID: 28396313). 28396313
MET D1228N Advanced Solid Tumor predicted - sensitive Altiratinib Preclinical Actionable In a preclinical study, Altiratinib (DCC-2701) inhibited activity of MET D1228N in an in vitro kinase assay (PMID: 26285778). 26285778
MET del exon14 MET D1228N Advanced Solid Tumor sensitive Glesatinib Preclinical - Cell line xenograft Actionable In a preclinical study, transformed cells expressing MET deletion exon 14 and MET D1228N were sensitive to Glesatinib (MGCD265) treatment, demonstrating cell growth inhibition in culture and 21% tumor regression in xenograft models (PMID: 28765324). 28765324
MET del exon14 MET D1228N lung squamous cell carcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, a patient with squamous cell lung cancer harboring a MET exon 14 skipping mutation was determined to have acquired MET D1228N after progression on Xalkori (crizotinib) therapy (PMID: 27343442). 27343442
MET amp MET del exon14 MET D1228N MET G1163R MET Y1230H MET Y1230S lung adenocarcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, a lung adenocarcinoma patient harboring MET deletion exon 14 and MET amplification demonstrated resistance to Xalkori (crizotinib), and the patient was found to have acquired MET Y1230H, MET D1228N, MET Y1230S, and MET G1163R (PMID: 28765324). 28765324
MET amp MET del exon14 MET D1228N MET G1163R MET Y1230H MET Y1230S lung adenocarcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, a patient with lung adenocarcinoma harboring MET deletion exon 14 responded to Xalkori (crizotinib), demonstrating a near complete response at 3 months, however, after 9 months progression ensued and a re-biospy identified MET del exon14, MET amplification, MET D1228N, MET Y1230H, MET Y1230S, and MET G1163R (PMID: 28522754). 28522754
MET amp MET del exon14 MET D1228N MET G1163R MET L1195V lung adenocarcinoma predicted - resistant Glesatinib Case Reports/Case Series Actionable In a clinical case study, a lung adenocarcinoma patient previously harboring MET amp, MET deletion exon 14, MET D1228N, MET Y1230H, MET Y1230S, and MET G1163R demonstrated a decrease in lesion size when treated with Glesatinib (MGCD265), however, progression ensued and plasma testing indicated the patient lost Y1230H and Y1230S, but acquired MET L1195V (PMID: 28765324). 28765324