ClinVar Miner

Submissions for variant NM_000248.3(MITF):c.952G>A (p.Glu318Lys) (rs149617956)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129682 SCV000184481 pathogenic Hereditary cancer-predisposing syndrome 2017-11-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Significant disease association in appropriately sized case-control study(ies)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000222278 SCV000271977 likely benign not specified 2019-01-17 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Invitae RCV000627790 SCV000283992 pathogenic Tietz syndrome; Waardenburg syndrome type 2A; Cutaneous malignant melanoma 8 2019-01-07 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 318 of the MITF protein (p.Glu318Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs149617956, ExAC 0.2%). This variant has been reported in individuals with cutaneous melanoma (PMID: 22012259, 22080950, 27473757) and renal cell carcinoma (PMID: 22012259). In a large case-control study involving ~4,000 cases and controls, individuals who carried this variant had a significantly increased risk of cutaneous melanoma (OR=2.19 CI: 1.41-3.45) (PMID: 22080950). Furthermore, in studies of over 30 families, this variant has been shown to display moderate segregation with melanoma (LOD = 2.7) (PMID: 22080950, 22012259, 23167872). ClinVar contains an entry for this variant (Variation ID: 29792). Experimental studies have shown that this missense change decreases the SUMOylation of MITF, leading to elevated transcription of target genes, and, in certain cell lines, increased colony forming potential (PMID: 22012259, 22080950, 23787126). In summary, this is a frequently observed variant that moderately segregates with disease, impacts MITF function, and is associated with a 2-fold increased risk of melanoma. Therefore, it has been classified as Pathogenic.
GeneDx RCV000484916 SCV000568597 pathogenic not provided 2018-08-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted MITF c.952G>A at the cDNA level, p.Glu318Lys (E318K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). Several case-control studies have revealed MITF Glu318Lys to be significantly associated with melanoma risk, particularly multiple primary melanomas (Bertolotto 2011, Yokoyama 2011, Ghiorzo 2013, Sturm 2014, Wadt 2015, Potrony 2016). In addition, this variant has been observed in individuals with a personal and/or family history of renal cell carcinoma (Bertolotto 2011, Ghiorzo 2013, Potrony 2016). Functional analyses of MITF Glu318Lys have demonstrated impaired sumoylation and differentially regulated expression of several MITF target genes in comparison to wild type protein (Bertolotto 2011, Yokoyama 2011, Grill 2013, Bonet 2017). MITF Glu318Lys was observed at an allele frequency of 0.25% (315/126,616) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the DNA binding regulation region and in a small-ubiquitin-like modifier (SUMO) consensus site (Bertolotto 2011, UniProt). Although in silico analysis predicts that this variant does not alter protein structure/function, published functional analysis supports a pathogenic effect. Based on currently available evidence, we consider this variant to be pathogenic.
Color RCV000129682 SCV000684704 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000022661 SCV000696089 likely pathogenic Cutaneous malignant melanoma 8 2019-02-21 criteria provided, single submitter clinical testing Variant summary: The variant, MITF c.952G>A (p.Glu318Lys) results in a conservative amino acid change located in the Myc-type, basic helix-loop-helix (bHLH) domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 288570 control chromosomes (gnomAD, Gromowski_2014, Yokoyama_2012 and Bertolotto_2011). This frequency is not significantly higher than expected for a pathogenic variant in MITF causing Melanoma and renal cell carcinoma risk (0.0014 vs 0.002), allowing no conclusion about variant significance. The variant c.952G>A has been reported in the literature in multiple individuals affected with Melanoma and renal cell carcinoma (Bertolotto_2011, Yokoyama_2012, Ghiorzo_2012, Potjer_2018). In a large case-control study, the variant co-segregated with melanoma in some but not all cases in the family indicating that the E318K is a possible intermediate risk variant (Yokoyama_2012) . In the same study the authors also observed that the individuals who carried the variant had significantly higher risk of developing melanoma (OR=2.19 CI: 1.41-3.45). Similarly, the carriers of this variant were reported to have a 5 fold increased risk of developing melanoma, renal cell carcinoma or both these cancers (OR = 5.55 (95% CI 2.59-12.91, Bertolotto_2011). These data indicate that the variant is very likely to be associated with disease. Experimental evidence suggest that this missense change leads to a SUMOylation- deficient MITF, transcriptional regulation of a subset of its target genes, increased migration, invasion and colony formation in stable melanoma cells (Bertolotto_2011). In a series of in vitro studies performed by Grill et al, the variant showed normal DNA binding ability but promoter specific effects on transcription of its target genes (Grill_2013). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. This variant was previously classified as a VUS by our laboratory in 2016. Based on the previous and additional emerging evidence outlined above, the variant appears to be a risk-factor for melanoma and/or renal cell carcinoma with supportive functional evidence. Therefore, it was classified as likely pathogenic.
Geisinger Autism and Developmental Medicine Institute,Geisinger Health System RCV000022661 SCV000804382 pathogenic Cutaneous malignant melanoma 8 2017-06-06 criteria provided, single submitter provider interpretation This variant was identified in a 12 year old female with moderate intellectual disability, borderline microcephaly, ADHD, speech disorder, stereotypy, constipation, narrow face, upturned nose, and mildly bowed upper lip. It is present in the gnomAD non-Finnish European population at 0.25%. This variant is a well-established risk factor for melanoma and renal cell carcinoma (OR 2.95-8.37, depending on family history) (Bertolotto, 2011; Ghiorzo, 2013; Wadt, 2015; Potrony, 2016). This variant was also present in the proband's mother who had melanoma diagnosed in her early 30s.
OMIM RCV000022661 SCV000043950 risk factor Cutaneous malignant melanoma 8 2011-11-13 no assertion criteria provided literature only
PreventionGenetics,PreventionGenetics RCV000222278 SCV000303141 uncertain significance not specified 2016-11-29 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000484916 SCV000840286 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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