ClinVar Miner

Submissions for variant NM_001354604.2(MITF):c.1273G>A (p.Glu425Lys) (rs149617956)

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Total submissions: 13
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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 2020-03-10 criteria provided, single submitter clinical testing The p.E318K pathogenic mutation (also known as c.952G>A), located in coding exon 9 of the MITF gene, results from a G to A substitution at nucleotide position 952. The glutamic acid at codon 318 is replaced by lysine, an amino acid with similar properties. This alteration is enriched in renal cell carcinoma (RCC) cohorts and confers up to a 5-fold risk for RCC; however, sample sizes from these studies were small and accurate risks are still being refined (Bertolotto C et al. Nature. 2011 Dec;480:94-8; Ghiorzo P et al. Pigment Cell Melanoma Res. 2013 Mar;26:259-62). This alteration does not appear to play a role in sporadic disease (Stoehr CG et al. Pathobiology. 2016 Mar;83:165-9). It was also independently linked to melanoma incidence by two simultaneous publications in a cohort of French patients and in a conglomerate cohort of patients from Australia and the United Kingdom (Bertolotto C et al. Nature. 2011 Dec;480:94-8; Yokoyama S et al. Nature. 2011 Dec;480:99-103). These studies identified approximately 2-5 fold increased odds ratio for developing melanoma in carriers of MITF p.E318K compared to healthy controls, a result that has been recapitulated in subsequent melanoma case-control studies (Ghiorzo P et al. Pigment Cell Melanoma Res. 2013 Mar;26:259-62; Bruno W et al. J. Am. Acad. Dermatol. 2016 Feb;74:325-32; Berwick M et al. Pigment Cell Melanoma Res. 2014 May;27:485-8; Potrony M et al. JAMA Dermatol. 2016 Apr;152:405-12; Mangas C et al. Br. J. Dermatol. 2016 Jul;175:1030-1037). This alteration segregates with melanoma in several families in a pattern that is consistent with a moderate penetrance allele and has been identified in numerous unselected control groups across studies (Bertolotto C et al. Nature. 2011 Dec;480:94-8; Yokoyama S et al. Nature. 2011 Dec;480:99-103; Ghiorzo P et al. Pigment Cell Melanoma Res. 2013 Mar;26:259-62; Mangas C et al. Br. J. Dermatol. 2016 Jul;175:1030-1037). In addition, this alteration has also been identified in numerous individuals in our internal cohort unaffected with RCC or melanoma (Ambry Internal Data). Functional analysis suggests that this variant prevents appropriate sumoylation which leads to differential binding and activation of MITF target genes (Yokoyama S et al. Nature. 2011 Dec;480:99-103; Grill C et al. Hum. Mol. Genet. 2013 Nov;22:4357-67). In addition this alteration as shown to affect cellular senescence further promoting melanoma development (Bonet C et al. J. Natl. Cancer Inst. 2017 08;109). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV001195106 SCV000271977 risk factor Melanoma 2020-03-04 criteria provided, single submitter clinical testing MITF c.952G>A (p.Glu318Lys variant, also referred to as Glu419Lys) in MITF has been associated with an increased risk of cutaneous melanoma. This variant has been observed in multiple ethnic backgrounds with highest frequencies in individuals of European ancestry (0.25%, Genome Aggregation Database (gnomAD); rs149617956) and is present in ClinVar (ID: 29792). Several large studies have reported an odds ratio of 1.7-5.5 for developing melanoma in heterozygous carriers (OR=2.19 [95% CI 1.41-3.45] Yokoyama 2011, OR=5.55 [95% CI 2.59-12.91] Bertolotto 2011, OR=1.7 [95% CI 1.1-2.6] Berwick 2011, OR=3.19 [95% CI 1.34-7.59] Castro-Vega 2016, OR=2.85 [95% CI 1.31-6.18] Ghiorzo 2013, OR=4.5 [95% CI 1.83-11.01] Potrony 2016). In vitro functional evidence suggests that the p.Glu318Lys variant reduces sumoylation of MITF, which in turn increases MITF transcriptional activity (Bertolotto 2011, Grill 2013, Yokoyama 2011). Therefore, this variant is not expected to cause highly penetrant Mendelian disease. In summary, this variant is an established risk factor for cutaneous melanoma.
Invitae RCV000627790 SCV000283992 pathogenic Tietz syndrome; Waardenburg syndrome type 2A; Cutaneous malignant melanoma 8 2020-10-28 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 Health, Inc RCV000129682 SCV000684704 likely pathogenic Hereditary cancer-predisposing syndrome 2020-08-25 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 318 of the MITF protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant decreases the SUMOylation of MITF, resulting in altered transcription of target genes and increased colony forming potential (PMID: 22012259, 22080950). This variant has been reported in many individuals affected with cutaneous melanoma (PMID: 22012259, 22080950, 23774529, 24638154, 24660985, 25943250, 26103950, 26775776, 26800492, 27473757) and renal cell carcinoma (PMID: 22012259). Multiple case-control studies have shown that this variant is associated with an increased risk of melanoma (OR = 2-5) (PMID: 22012259, 22080950, 25803691, 26650189). In addition, this variant is associated with an increased risk of renal cell carcinoma (OR= 5.19, CI:1.37–16.87) (PMID: 22012259). In a study of more than 30 families, this variant has been shown to have a moderate segregation with melanoma with LOD of 2.7 (PMID: 22080950). This variant is frequently observed in the general population and has been identified in 386/282776 chromosomes by the Genome Aggregation Database (gnomAD). In summary, this variant alters MITF protein function and is associated with an increased risk of melanoma and renal cell carcinoma. Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000484916 SCV001447728 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000129682 SCV001449026 pathogenic Hereditary cancer-predisposing syndrome 2019-09-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000484916 SCV001502449 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
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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