VCV000029792.124 - ClinVar

NM_001354604.2(MITF):c.1273G>A (p.Glu425Lys)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic; risk factor
Pathogenic (25); Likely pathogenic (8)

34 out of 38 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001354604.2(MITF):c.1273G>A (p.Glu425Lys)

Variation ID: 29792 Accession: VCV000029792.124

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p13 3: 69964940 (GRCh38) [ NCBI UCSC ] 3: 70014091 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 19, 2017	Jul 27, 2026	Jun 1, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_001354604.2:c.1273G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001341533.1:p.Glu425Lys	missense
NM_000248.4:c.952G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000239.1:p.Glu318Lys	missense
NM_001184967.2:c.1099G>A	NP_001171896.1:p.Glu367Lys	missense
NM_001354605.2:c.1270G>A	NP_001341534.1:p.Glu424Lys	missense
NM_001354606.2:c.1252G>A	NP_001341535.1:p.Glu418Lys	missense
NM_001354607.2:c.1204G>A	NP_001341536.1:p.Glu402Lys	missense
NM_001354608.2:c.1099G>A	NP_001341537.1:p.Glu367Lys	missense
NM_006722.3:c.1252G>A	NP_006713.1:p.Glu418Lys	missense
NM_198158.3:c.934G>A	NP_937801.1:p.Glu312Lys	missense
NM_198159.3:c.1255G>A	NP_937802.1:p.Glu419Lys	missense
NM_198177.3:c.1207G>A	NP_937820.1:p.Glu403Lys	missense
NM_198178.3:c.766G>A	NP_937821.2:p.Glu256Lys	missense
NC_000003.12:g.69964940G>A
NC_000003.11:g.70014091G>A
NG_011631.1:g.230459G>A
LRG_776:g.230459G>A
LRG_776t1:c.952G>A	LRG_776p1:p.Glu318Lys

... more HGVS ... less HGVS

Protein change

E318K, E419K, E312K, E403K, E402K, E256K, E418K, E425K, E367K, E424K

Other names

Canonical SPDI

NC_000003.12:69964939:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00080 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00294

1000 Genomes Project 30x 0.00078

Exome Aggregation Consortium (ExAC) 0.00133

Trans-Omics for Precision Medicine (TOPMed) 0.00179

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00223

1000 Genomes Project 0.00080

The Genome Aggregation Database (gnomAD), exomes 0.00136

The Genome Aggregation Database (gnomAD) 0.00158

The Genome Aggregation Database (gnomAD) 0.00160

Links

ClinGen: CA128649 Genetic Testing Registry (GTR): GTR000595964 Genetic Testing Registry (GTR): GTR000613325 Genetic Testing Registry (GTR): GTR000613326 OMIM: 156845.0009 dbSNP: rs149617956 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MITF		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1363	1394

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Melanoma, cutaneous malignant, susceptibility to, 8	Pathogenic/Likely pathogenic (13)	criteria provided, multiple submitters, no conflicts	Dec 1, 2025	RCV000022661.36
Hereditary cancer-predisposing syndrome	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 3, 2025	RCV000129682.23
not specified	risk factor (1)	no assertion criteria provided	Nov 25, 2019	RCV000222278.12
not provided	Pathogenic/Likely pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jun 1, 2026	RCV000484916.59
Melanoma, cutaneous malignant, susceptibility to, 8 Tietz syndrome Waardenburg syndrome type 2A	Pathogenic (1)	criteria provided, single submitter	Feb 3, 2026	RCV000627790.14
Melanoma	risk factor (1)	criteria provided, single submitter	Mar 4, 2020	RCV001195106.7
Melanoma, cutaneous malignant, susceptibility to, 8 Waardenburg syndrome type 2A	Likely pathogenic (2)	criteria provided, single submitter	Nov 18, 2025	RCV001535706.6
Tietz syndrome	Pathogenic (1)	criteria provided, single submitter	May 4, 2022	RCV002247378.3
Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness Melanoma, cutaneous malignant, susceptibility to, 8 Tietz syndrome Waardenburg syndrome type 2A	Pathogenic (1)	criteria provided, single submitter	Jan 9, 2024	RCV002490402.4
MITF-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 20, 2025	RCV005249995.2
Familial melanoma	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 20, 2023	RCV005364885.2
Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness	Pathogenic (1)	criteria provided, single submitter	Apr 30, 2025	RCV006684515.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
risk factor (Mar 04, 2020) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	Melanoma	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000271977.3 First in ClinVar: May 29, 2016 Last updated: Jul 03, 2020	Publications: PubMed (13) PubMed: 22012259‚ 22080950‚ 23167872‚ 23774529‚ 23787126‚ 24352080‚ 24406078‚ 24767713‚ 25407435‚ 25803691‚ 26650189‚ 26775776‚ 27680874 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 5

Pathogenic (Apr 03, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Melanoma, cutaneous malignant, susceptibility to, 8	Illumina Laboratory Services, Illumina Accession: SCV004801538.1 First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024	Comment: show The MITF c.952G>A p.(Glu318Lys) variant, also referred to as c.1255G>A p.(Glu419Lys), is associated with increased risk for melanoma. Bertolotto et al. (2011) identified the p.(Glu318Lys) variant in a heterozygous state in 17 of 603 melanoma patients who were negative for CDKN2A and CDK4 variants. Carriers of this variant exhibited a significant increase in melanoma risk when compared to the control population, with an odds ratio of 4.78 [95% confidence interval: 2.05-11.75). The p.(Glu318Lys) variant was also found to co-segregate with melanoma in three melanoma-prone families. Yokoyama et al. (2011) identified 31 unrelated cases carrying the p.Glu318Lys variant who had at least one first- or second-degree relative diagnosed with melanoma. In 21 of 43 families, the variant was found in all affected individuals who were available for testing. Functional analysis showed that MITF encoded by the p.(Glu318Lys) variant allele had impaired sumoylation and differentially regulated several MITF targets. Berwick et al. (2014) assessed the p.(Glu318Lys) variant in 1194 cases and 2430 controls and found a positive association between the variant and the risk of melanoma, which was independent of the classical melanoma risk factors. Several additional studies have also reported a significantly increased melanoma risk in carriers of the variant (Ghiorzo et al. 2013; Potrony et al. 2015) or higher frequency of the variant in cases versus controls (Wadt et al. 2015). This variant has also been associated with an increased risk of renal cell carcinoma (Bertolotto et al. 2011; Ghiorzo et al. 2013; Potrony et al. 2016). The highest frequency of this allele in the Genome Aggregation Database is 0.002456 in the European (non-Finnish) population (version 2.1.1). Based on the available evidence, the c.952G>A p.(Glu318Lys) variant is classified as a pathogenic risk allele for melanoma. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Nov 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV000184481.8 First in ClinVar: Aug 06, 2014 Last updated: Jan 13, 2025	Publications: PubMed (24) PubMed: 22012259‚ 22080950‚ 22158021‚ 23167872‚ 23774529‚ 23787126‚ 23802662‚ 24290354‚ 24406078‚ 2440678‚ 24660985‚ 24767713‚ 25803691‚ 25975176‚ 26650189‚ 26775776‚ 26800492‚ 26999813‚ 27473757‚ 27680874‚ 28376192‚ 29706638‚ 30414346‚ 37635363 Comment: show 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. Several case-control studies have identified an approximately 2-fold increased odds ratio for developing melanoma in carriers of MITF p.E318K compared to healthy controls (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.). In addition, this variant has also been identified in numerous individuals in our internal cohort unaffected with RCC or melanoma (Ambry Internal Data). Though some studies have suggested an increase in risk of renal cell carcinoma, current evidence is insufficient to support a clear increase in risk of renal cancer in carriers of p.E318K over that of the general population (Bertolotto C et al; Guhan S et al. Sci Rep. 2020 Oct 13;10(1):17051). 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 variant is shown to affect cellular senescence further promoting melanoma development (Bonet C et al. J. Natl. Cancer Inst. 2017 08;109). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jan 20, 2024) C Contributing to aggregate classification	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Melanoma, cutaneous malignant, susceptibility to, 8	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV002012371.5 First in ClinVar: Nov 11, 2021 Last updated: Oct 12, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Mar 24, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Assertion Criteria Germline)	Familial melanoma (Autosomal dominant inheritance)	Department of Genomics, ADN Uruguay Accession: SCV007097388.1 First in ClinVar: Nov 08, 2025 Last updated: Nov 08, 2025	Publications: PubMed (2) PubMed: 22080950‚ 23787126 Comment: show This missense variant in MITF (c.1273G>A, p.Glu425Lys) has been reported in individuals with familial and sporadic melanoma (PMID:23787126;PMID:22080950). It affects a conserved residue and is predicted to be damaging by multiple in-silico tools (PP3). The variant is rare in population databases (PM2) and meets ACMG/AMP criteria for Pathogenic classification. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Family history: no Sex: female Platform type: next-generation sequencing

Likely pathogenic (Nov 18, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Melanoma, cutaneous malignant, susceptibility to, 8 Waardenburg syndrome type 2A Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Accession: SCV007107097.1 First in ClinVar: May 23, 2026 Last updated: May 23, 2026	Publications: PubMed (5) PubMed: 22012259‚ 22080950‚ 23167872‚ 23787126‚ 27473757 Comment: show The following ACMG criteria has been used: PS3_SUP; PS4; PP1 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Sex: male

Likely pathogenic (Dec 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002550869.6 First in ClinVar: Jul 27, 2022 Last updated: Jan 03, 2026	Publications: PubMed (3) PubMed: 22012259‚ 22080950‚ 34289891 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Oct 10, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004224971.3 First in ClinVar: Jan 06, 2024 Last updated: Jan 11, 2026	Publications: PubMed (8) PubMed: 22012259‚ 22080950‚ 23167872‚ 23787126‚ 25803691‚ 28376192‚ 36863448‚ 37635363 Comment: show PS3_supporting, PS4 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 4

Pathogenic (Feb 03, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Melanoma, cutaneous malignant, susceptibility to, 8 Waardenburg syndrome type 2A Tietz syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000283992.13 First in ClinVar: Jul 01, 2016 Last updated: Feb 23, 2026	Publications: PubMed (6) PubMed: 22012259‚ 22080950‚ 23167872‚ 23787126‚ 27473757‚ 28492532 Comment: show This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 318 of the MITF protein (p.Glu318Lys). This variant is present in population databases (rs149617956, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with cutaneous melanoma (PMID: 22012259, 22080950, 23167872, 27473757). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29792). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MITF protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MITF function (PMID: 22012259, 22080950, 23787126). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jan 03, 2026) C Contributing to aggregate classification	criteria provided, single submitter (DASA Assertion Criteria)	not provided	Dasa Accession: SCV007598789.1 First in ClinVar: May 30, 2026 Last updated: May 30, 2026	Publications: PubMed (14) PubMed: 22012259‚ 22080950‚ 23167872‚ 23774529‚ 23787126‚ 24406078‚ 25803691‚ 26650189‚ 27473757‚ 27680874‚ 28376192‚ 31465090‚ 32054529‚ 33240314 Comment: show NM_001354604.2(MITF):c.1273G>A (p.Glu425Lys) is a missense variant that results in the substitution of glutamic acid with lysine. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 22012259; PMID: 22080950; PMID: 23167872; PMID: 27473757; PMID: 23787126). This variant has been recurrently observed in individuals with related phenotype (PMID: 22012259; PMID: 22080950; PMID: 23167872; PMID: 27473757; PMID: 23787126). Based on the available data, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Dec 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Melanoma, cutaneous malignant, susceptibility to, 8	Otogenetics Accession: SCV007600227.1 First in ClinVar: May 30, 2026 Last updated: May 30, 2026	Publications: PubMed (7) PubMed: 22012259‚ 22080950‚ 23787126‚ 26775776‚ 27473757‚ 28376192‚ 30414346 Comment: show PS3_Moderate: Well-established in vitro and in vivo functional studies supportive of damaging effect on the gene product, with low residual enzymatic activity relative to wild-type reported (PMID: 22012259, 22080950, 23787126, 28376192); PS4: Prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls: one case-control studies investigating MITF missense mutations indicate this mutation has an OR > 2, with valid confidence intervals and p-values < 0.005 (PMID: 22012259, 22080950, 26775776, 27473757); PM2: Maximum gnomAD MAF of 0.246% in European-Non Finnish (NFE) subpopulation (<0.246% threshold); PP1: Cosegregation with melanoma across multiple affected family members in over 10 unrelated families (PMID: 22012259, 22080950); PP4: Variant reported in patients with highly specific phenotype for disease fitting (PMID: 22012259, 22080950, 27473757, 30414346) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Melanoma, cutaneous malignant, susceptibility to, 8 (Autosomal dominant inheritance)	CHARM Consortium Accession: SCV007602332.1 First in ClinVar: Jun 14, 2026 Last updated: Jun 14, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1 Sex: female Comment on evidence: Observed in 1 individual with germline variant in PALB2 and LZTR1

Pathogenic (Sep 17, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001449026.1 First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 13 Test name: Healthy Oregon Project

Pathogenic (Mar 02, 2020) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000568597.4 First in ClinVar: Apr 27, 2017 Last updated: Dec 19, 2017	Comment: show Published functional studies demonstrate a damaging effect: impaired sumoylation and differentially regulated expression of several MITF target genes (Bertolotto 2011, Yokoyama 2011, Grill 2013, Bonet 2017); Most case control studies suggest variant is associated with melanoma (OR=2.09-4.78), with an enrichment of the variant in patients with multiple primary melanomas and those with a family history of melanoma (Bertolotto 2011, Yokoyama 2011, Ghiorzo 2013, Gromowski 2014, Wadt 2015, Potrony 2016); Overrepresented among renal cell carcinoma cases (OR=5.19) and in individuals diagnosed with both melanoma and renal cell carcinoma (OR=14.46) (Bertolotto 2011); This variant is associated with the following publications: (PMID: 23787126, 27473757, 28125078, 28825054, 31034483, 22012259, 22080950, 28376192, 23167872, 24767713, 25803691, 26650189, 23774529, 24406078, 27153395, 27680874, 26800492, 27181379, 26775776, 26999813, 26999650, 27899189, 27720647, 28787086, 28152038, 24660985, 24290354, 23802662, 23046018, 22158021, 2440678, 24352080, 29485552, 29706638, 29506128, 30759220, 31201024, 30414346, 32054529, 31465090, 33240314) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Nov 02, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502905.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (18) PubMed: 22012259‚ 22080950‚ 23167872‚ 23774529‚ 23787126‚ 24406078‚ 25803691‚ 27153395‚ 27680874‚ 28125078‚ 28152038‚ 28376192‚ 28825054‚ 29506128‚ 30414346‚ 31465090‚ 32054529‚ 33240314 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 2 Secondary finding: no Platform type: NGS

Pathogenic (May 04, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Tietz syndrome	Mendelics Accession: SCV002517617.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Sep 26, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Melanoma, cutaneous malignant, susceptibility to, 8	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: HudsonAlpha-COAGS Accession: SCV002575023.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022	Comment: show PS3_Moderate, PS4, PP1_Moderate, PP3 (less) Observation: 1 Collection method: research Allele origin: unknown Affected status: unknown more Observation 1 Collection method: research Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1

Likely pathogenic (Jul 01, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Melanoma, cutaneous malignant, susceptibility to, 8	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003806735.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: show ACMG classification criteria: PS3 supporting, PS4 strong, PP1 moderated (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Clinical Features: Breast carcinoma (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 8	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV004046260.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: show This variant is a recurrent alteration that has been reported as a heterozygous change in multiple individuals with cutaneous melanoma, renal cell carcinoma, or both cancers (PMID: 22012259, 22012259, 22080950, 27473757). A large case-controlled study observed that individuals with the p.Glu419Lys variant had a significantly increased risk of cutaneous melanoma (PMID: 22080950). Additionally, several studies showed the p.Glu419Lys variant had moderate co-segregation with melanoma, supporting the theory that this variant is a moderate penetrance melanoma risk factor (PMID: 22080950, 22012259, 23167872). Experimental studies have shown that the p.Glu419Lys variant leads to abnormal transcription of target genes and, in certain cell lines, increased colony forming potential (PMID: 22012259, 22080950, 23787126). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.1% (386/282776). In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.1255G>A (p.Glu419Lys) variant is classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Mar 30, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Melanoma, cutaneous malignant, susceptibility to, 8	Baylor Genetics Accession: SCV004192590.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Feb 17, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Melanoma, cutaneous malignant, susceptibility to, 8	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005382163.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: show ACMG Criteria: PS3, PS4, PP1, PP5; Variant was found in heterozygous state. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Breast carcinoma (present) , Family history of cancer (present)

Pathogenic (Jan 09, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Tietz syndrome Waardenburg syndrome type 2A Melanoma, cutaneous malignant, susceptibility to, 8 Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Fulgent Genetics, Fulgent Genetics Accession: SCV002785503.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Aug 06, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	not provided	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV004563072.2 First in ClinVar: Feb 20, 2024 Last updated: Mar 11, 2025	Comment: show The MITF c.952G>A; p.Glu318Lys variant (rs149617956, ClinVar variation ID: 29792) is reported in the literature in patients affected with renal cell carcinoma and sporadic and familial melanoma (Bertolotto 2011, Yokoyama 2011, Backman 2021, Bonet 2017). This variant is found in the general population with an overall allele frequency of 0.14% (386/282776 alleles) in the Genome Aggregation Database (v2.1.1). In vitro and in vivo functional analyses demonstrate the glutamic acid to lysine amino acid change results in defective SUMOylation of the MITF protein causing defective cellular senescence (Bertolotto 2011, Bonet 2017). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.438). Based on available information, this variant is considered to be pathogenic. References: Bertolotto, C et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480, 94-98 (2011). PMID: 22012259 Yokoyama S et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011;480(7375):99-103. Published 2011 Nov 13. PMID: 22080950 Backman JD et al. Exome sequencing and analysis of 454,787 UK Biobank participants. Nature. 2021;599(7886):628-634. PMID: 34662886 Bonet C et al. Deciphering the Role of Oncogenic MITFE318K in Senescence Delay and Melanoma Progression. J Natl Cancer Inst. 2017;109(8). PMID: 28376192 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jun 06, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Melanoma, cutaneous malignant, susceptibility to, 8	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System Accession: SCV000804382.3 First in ClinVar: May 26, 2018 Last updated: Apr 13, 2025	Publications: PubMed (4) PubMed: 22012259‚ 23167872‚ 25803691‚ 26650189 Comment: show 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. (less) Observation: 2 Observation 1 Collection method: provider interpretation Allele origin: maternal Affected status: unknown Clinical Features: Intellectual disability, moderate (present) , Mild microcephaly (present) , Attention deficit hyperactivity disorder (present) , Neurological speech impairment (present) , Stereotypy (present) , Constipation (present) , Narrow face (present) , Anteverted nares (present) Age: 10-19 years Sex: female Secondary finding: yes Testing laboratory: GeneDx Date variant was reported to submitter: 2017-05-06 Testing laboratory interpretation: Pathogenic Observation 2 Collection method: clinical testing Allele origin: maternal Affected status: unknown Number of individuals with the variant: 1 Clinical Features: Intellectual disability, moderate (present) , Mild microcephaly (present) , Attention deficit hyperactivity disorder (present) , Neurological speech impairment (present) , Stereotypy (present) , Constipation (present) , Narrow face (present) , Anteverted nares (present) Age: 10-19 years Sex: female Testing laboratory: GeneDx Date variant was reported to submitter: 2017-05-06 Testing laboratory interpretation: Pathogenic

Likely pathogenic (Oct 23, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided (Autosomal unknown)	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447728.2 First in ClinVar: Nov 28, 2020 Last updated: Apr 13, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Clinical Features: Melanoma (present) , Malignant melanoma of skin (present) Sex: male

Pathogenic (Sep 20, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Familial melanoma	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV005914547.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Publications: PubMed (5) PubMed: 22012259‚ 22080950‚ 23167872‚ 28376192‚ 34289891 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (May 02, 2024) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Melanoma, cutaneous malignant, susceptibility to, 8	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696089.6 First in ClinVar: Dec 19, 2017 Last updated: Jun 14, 2025	Publications: PubMed (11) PubMed: 22012259‚ 22080950‚ 23167872‚ 23787126‚ 24406078‚ 24767713‚ 28125078‚ 30414346‚ 33051548‚ 34289891‚ 34662886 Comment: show Variant summary: Variant summary: 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. Three 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 262840 control chromosomes. This frequency is not higher than the estimated maximum 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 (e.g. Bertolotto_2011, Yokoyama_2012, Ghiorzo_2012, Potjer_2018), where the variant was noted to segregate with the disease in some, but not all families, indicating that the E318K is a possible intermediate risk variant. In a large case-control study authors observed that 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). The variant was also observed in individuals with personal and/or family history of breast cancer and other tumor phenotypes (Oliveira_2021), however a meta-analysis found minimal evidence for E318K's contribution to non-melanoma cancer risk (Guhan_2020). Experimental evidence suggests that this missense change causes decreased SUMOylation of MITF, resulting in an increased transcriptional activity with enhanced 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 had promoter specific effects on transcription of its target genes (Grill_2013). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=9) / likely pathogenic (n=3) or as a risk factor (n=2). Based on the 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 pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (May 18, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Molecular Diagnostics Laboratory, Catalan Institute of Oncology Accession: SCV006324484.1 First in ClinVar: Sep 22, 2025 Last updated: Sep 22, 2025	Other databases https://spadahc.ciberisciii.es/v… https://spadahc.ciberisciii.es/variant/GRCH37/3%2070014091%20G/A Comment: show PS4, PP1_VeryStrong c.952G>A, located in exon 9 of the MITF gene, is predicted to result in the substitution of glutamic acid by lysine at codon 318, p.(Glu318Lys). This variant is found in 346/268238 alleles at a frequency of 0.13% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.438) is undetermined regarding the effect that it may have on protein function according to Pejaver 2022 thresholds (PMID:36413997). Functional analyses of p.E318K have shown that it impairs sumoylation and alters MITF transcriptional activity in transfected melanoma cell lines (PMID: 22080950, 22012259, 23787126). Several case-control studies have confirmed an association between this mutation and the risk of melanoma and or renal cell carncinoma (OR=2.19 [95% CI 1.41-3.45 P=0,0003] PMID:22080950, OR=4,78 [95% CI 2,05-11,75 p<0,0001] PMID: 22012259, OR=1.7 [95% CI 1.1-2.7 p=0,03] PMID: 24406078, OR=2.85 [95% CI 1.31-6.18 p=0.011] PMID: 23167872, OR=3,3 [95% CI 1.43-7,42 P<0,01] PMID: 26650189, OR = 3,16 PMID: 25803691) (PS4). This variant cosegregates in multiple melanoma families with a LOD score: 2,7, equivalent to LR:501 (PMID:22080950) (PP1_veryStrong). This variant has been reported in the ClinVar database (17x pathogenic, 7x likely pathogenic), in the LOVD database (1x pathogenic). Based on currently available information, the variant c.952G>A should be considered a pathogenic variant according to ACMG/AMP classification guidelines. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

pathogenic (Sep 12, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria)	not provided	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002774816.2 First in ClinVar: Dec 31, 2022 Last updated: Dec 07, 2025	Comment: show The MITF c.952G>A (p.Glu318Lys) variant has been reported in the published literature in multiple individuals with melanoma and/or renal cell carcinoma (PMID: 22012259 (2011), 22080950 (2011), 24638154 (2014), 26775776 (2016), 26800492 (2016), 27473757 (2016), 30414346 (2019), 32054529 (2020), 35441217 (2022), 36863448 (2023), 37635363 (2024), 37864521 (2024), 39089886 (2024), 39315505 (2025)), and multiple case-control studies have shown that this variant is associated with an increased risk for melanoma and/or renal cell carcinoma (PMID: 22012259 (2011), 22080950 (2011), 23167872 (2013), 25803691 (2015), 26650189 (2016)). In addition, functional studies have shown that this variant causes MITF protein overactivity (PMID: 22012259 (2011), 22080950 (2011), 23787126 (2013)). Based on the available information, this variant is classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Sep 03, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary cancer-predisposing syndrome	Color Diagnostics, LLC DBA Color Health Accession: SCV000684704.8 First in ClinVar: Feb 19, 2018 Last updated: Feb 15, 2026	Publications: PubMed (14) PubMed: 22012259‚ 22080950‚ 23774529‚ 24638154‚ 24660985‚ 25943250‚ 26103950‚ 26775776‚ 26800492‚ 27473757‚ 27680874‚ 28125078‚ 28376192‚ 30414346 Comment: show 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. 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, 28376192). This variant has been reported in multiple individuals affected with cutaneous melanoma (PMID: 22012259, 22080950, 23774529, 24638154, 24660985, 25943250, 26103950, 26775776, 26800492, 27473757, 30414346), Ewing sarcoma (PMID: 28125078), pheochromocytomas/paragangliomas (PMID: 27680874), and renal cell carcinoma (PMID: 22012259). Multiple large case-control studies have shown that this variant is associated with an increased risk of melanoma (OR 1.7-5.5PMID: 22012259, 22080950, 25803691, 26650189, 26775776). 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). Based on the available evidence, this variant is considered a lower penetrance risk allele and is classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Likely pathogenic (Nov 04, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines 2015 PMID 25741868)	Melanoma, cutaneous malignant, susceptibility to, 8	OLLIN Analises Genomicas, OLLIN Accession: SCV007520810.1 First in ClinVar: Mar 28, 2026 Last updated: Mar 28, 2026	Publications: PubMed (6) PubMed: 22012259‚ 22080950‚ 23167872‚ 23787126‚ 27473757‚ 29506128 Comment: show The missense variant (chr3:69964940 G>A), located in exon 9 (of 9), is reported in ClinVar (VCV000029792.116) and gnomAD v4.1 non-UKB with an allele frequency of 0.16%, and described in the scientific literature in patients with melanoma and pancreatic cancer (PMID: 22012259, 22080950, 23787126, 23167872, 27473757, 29506128, 23167872). In silico analysis is inconclusive regarding the impact of this variant; however, functional studies suggest that this variant affects protein function (PMID: 22012259, 22080950, 23787126). Based on the currently available evidence, this variant has been classified as likely pathogenic (PS3_P, PS4, PP1). (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1 Sex: male Geographic origin: Brazil

Pathogenic (Aug 20, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	MITF-related disorders	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV005900649.2 First in ClinVar: Mar 29, 2025 Last updated: Mar 28, 2026	Publications: PubMed (20) PubMed: 10578055‚ 18510545‚ 20127975‚ 22012259‚ 22080950‚ 23167872‚ 23774529‚ 23787126‚ 25433395‚ 25803691‚ 26892650‚ 27473757‚ 27889061‚ 29706638‚ 32054529‚ 34289891‚ 38439523‚ 666627‚ 9158138‚ 9279758 Comment: show This variant results in a c.952G>A (p.Glu318Lys) and a c.1255G>A (p.Glu419Lys) change in alternate transcripts (NM_000248.4, NM_198159.2). The c.1273G>A (p.Glu425Lys) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. This is a recurrent variant that has been reported as a heterozygous change in individuals with cutaneous melanoma and/or renal cell carcinoma (PMID: 22012259, 22080950, 27473757). A large case-controlled study involving approximately 4,000 participants observed that individuals with the c.1273G>A (p.Glu425Lys) variant had a significantly increased risk of cutaneous melanoma (OR=2.19 CI: 1.41-3.45) (PMID: 22080950). Additionally, several studies of families harboring this variant showed moderate co-segregation with melanoma (LOD = 2.7), providing evidence to support c.1273G>A (p.Glu425Lys) as an intermediate penetrance melanoma risk variant (PMID: 22080950, 22012259, 23167872). Experimental studies have shown that this missense change decreases the SUMOylation of MITF, leading to elevated transcription of target genes and increased colony forming potential in certain cell lines (PMID: 22012259, 22080950, 23787126). The c.1273G>A (p.Glu425Lys) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.3% (4491/1614114), including 10 homozygotes. Based on the available evidence, c.1273G>A (p.Glu425Lys) is classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Apr 30, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (Autosomal recessive inheritance)	First Genomix Gene Laboratory, Genetic Diagnostics Department Accession: SCV007581087.1 First in ClinVar: May 03, 2026 Last updated: May 03, 2026	Comment: show As part of Carrier Screening testing performed at First Genomix, this variant was identified in a heterozygous state in a patient who is not affected with this condition. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no Number of individuals with the variant: 1

Pathogenic (Jun 01, 2026) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001502449.36 First in ClinVar: Mar 14, 2021 Last updated: Jul 27, 2026	Comment: show MITF: PP1:Strong, PS4, PM1, PS3:Moderate (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 23

risk factor (Nov 13, 2011) N Not contributing to aggregate classification	no assertion criteria provided	MELANOMA, CUTANEOUS MALIGNANT, SUSCEPTIBILITY TO, 8	OMIM Accession: SCV000043950.3 First in ClinVar: Apr 04, 2013 Last updated: Apr 15, 2023	Publications: PubMed (2) PubMed: 22012259‚ 22080950 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: Bertolotto et al. (2011) identified a c.952G-A transition (c.952G-A, NM_000248.3) in the MITF gene (isoform MITF-M), resulting in a glu-to-lys substitution at codon 318 (E318K). … (more) Bertolotto et al. (2011) identified a c.952G-A transition (c.952G-A, NM_000248.3) in the MITF gene (isoform MITF-M), resulting in a glu-to-lys substitution at codon 318 (E318K). This missense mutation was found at increased frequency in the germline of individuals with melanoma or renal cell carcinoma and at much increased frequency in individuals with both melanoma and renal cell carcinoma compared with controls. The overall allele frequency in controls was 0.003, in patients with melanoma and/or renal cell carcinoma it was 0.016, and among individuals with both melanoma and renal cell carcinoma it was 0.040. Yokoyama et al. (2011) independently identified the E318K mutation in the MITF gene (isoform MITF-M) as increasing the risk of melanoma in both families and sporadic cases. The variant cosegregated with melanoma in some, but not all, cases of melanoma in the initial family identified, but linkage analysis of 31 families subsequently identified to carry the variant generated a lod score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. Yokoyama et al. (2011) also showed that E318K prevents MITF sumoylation and results in differential expression of MITF target genes. (less)

risk factor (Nov 25, 2019) N Not contributing to aggregate classification	no assertion criteria provided	not specified	PreventionGenetics, part of Exact Sciences Accession: SCV000303141.3 First in ClinVar: Oct 02, 2016 Last updated: Dec 22, 2021	Publications: PubMed (1) PubMed: 22012259 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

not provided (-) N Not contributing to aggregate classification	no classification provided	Melanoma, cutaneous malignant, susceptibility to, 8 Waardenburg syndrome type 2A Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749790.3 First in ClinVar: Jul 18, 2021 Last updated: Apr 13, 2025	Comment: show Variant interpreted as Pathogenic and reported on 10-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Observation: 1 Collection method: phenotyping only Allele origin: unknown Affected status: unknown more Observation 1 Collection method: phenotyping only Allele origin: unknown Affected status: unknown Clinical Features: Breast carcinoma (present) Indication for testing: Diagnostic Age: 50-59 years Sex: female Platform type: Gene Panel Sequencing Testing laboratory: Labcorp Genetics (formerly Invitae), Labcorp Date variant was reported to submitter: 2020-10-29 Testing laboratory interpretation: Pathogenic

not provided (-) N Not contributing to aggregate classification	no classification provided	not provided	GenomeConnect, ClinGen Accession: SCV000840286.3 First in ClinVar: Oct 13, 2018 Last updated: Apr 13, 2025	Comment: show Variant identified in multiple registry participants. Variant interpreted as Likely pathogenic and reported on 01-03-2018 by Lab or GTR ID 505849 an interpreted as Pathogenic and reported on 09-18-2017 by Lab or GTR ID 61756. 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. (less) Observation: 2 Observation 1 Collection method: phenotyping only Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Clinical Features: Abnormality of eye movement (present) , Myopia (present) , Hyperpigmentation of the skin (present) Age: 40-49 years Sex: female Platform type: Gene Panel Sequencing Testing laboratory: Color Diagnostics, LLC DBA Color Health Date variant was reported to submitter: 2018-01-03 Testing laboratory interpretation: Likely pathogenic Observation 2 Collection method: phenotyping only Allele origin: unknown Affected status: unknown Number of individuals with the variant: 1 Clinical Features: Abnormality of the chin (present) , Orofacial cleft (present) , Abnormal facial shape (present) , Abnormal hair morphology (present) , Abnormal oral cavity morphology (present) , Abnormality of the mouth (present) , Abnormality of the neck (present) , Abnormality of the nose (present) , Abnormal skull morphology (present) , Oral-pharyngeal dysphagia (present) , Abnormality of eye movement (present) , Abnormality of globe size (present) , Abnormality iris morphology (present) , Abnormal lens morphology (present) , Abnormality of vision (present) , Myopia (present) , Hypermetropia (present) , Abnormal optic nerve morphology (present) , Abnormal retinal morphology (present) , Ptosis (present) , Cardiac arrhythmia (present) , Renal neoplasm (present) Indication for testing: Diagnostic Age: 30-39 years Sex: male Platform Type: Gene Panel Sequencing Testing laboratory: Ambry Genetics Date variant was reported to submitter: 2017-09-18 Testing laboratory interpretation: Pathogenic

Comment:

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.

Comment:

The MITF c.952G>A p.(Glu318Lys) variant, also referred to as c.1255G>A p.(Glu419Lys), is associated with increased risk for melanoma. Bertolotto et al. (2011) identified the p.(Glu318Lys) variant in a heterozygous state in 17 of 603 melanoma patients who were negative for CDKN2A and CDK4 variants. Carriers of this variant exhibited a significant increase in melanoma risk when compared to the control population, with an odds ratio of 4.78 [95% confidence interval: 2.05-11.75). The p.(Glu318Lys) variant was also found to co-segregate with melanoma in three melanoma-prone families. Yokoyama et al. (2011) identified 31 unrelated cases carrying the p.Glu318Lys variant who had at least one first- or second-degree relative diagnosed with melanoma. In 21 of 43 families, the variant was found in all affected individuals who were available for testing. Functional analysis showed that MITF encoded by the p.(Glu318Lys) variant allele had impaired sumoylation and differentially regulated several MITF targets. Berwick et al. (2014) assessed the p.(Glu318Lys) variant in 1194 cases and 2430 controls and found a positive association between the variant and the risk of melanoma, which was independent of the classical melanoma risk factors. Several additional studies have also reported a significantly increased melanoma risk in carriers of the variant (Ghiorzo et al. 2013; Potrony et al. 2015) or higher frequency of the variant in cases versus controls (Wadt et al. 2015). This variant has also been associated with an increased risk of renal cell carcinoma (Bertolotto et al. 2011; Ghiorzo et al. 2013; Potrony et al. 2016). The highest frequency of this allele in the Genome Aggregation Database is 0.002456 in the European (non-Finnish) population (version 2.1.1). Based on the available evidence, the c.952G>A p.(Glu318Lys) variant is classified as a pathogenic risk allele for melanoma.

Comment:

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. Several case-control studies have identified an approximately 2-fold increased odds ratio for developing melanoma in carriers of MITF p.E318K compared to healthy controls (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.). In addition, this variant has also been identified in numerous individuals in our internal cohort unaffected with RCC or melanoma (Ambry Internal Data). Though some studies have suggested an increase in risk of renal cell carcinoma, current evidence is insufficient to support a clear increase in risk of renal cancer in carriers of p.E318K over that of the general population (Bertolotto C et al; Guhan S et al. Sci Rep. 2020 Oct 13;10(1):17051). 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 variant is shown to affect cellular senescence further promoting melanoma development (Bonet C et al. J. Natl. Cancer Inst. 2017 08;109). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Comment:

This missense variant in MITF (c.1273G>A, p.Glu425Lys) has been reported in individuals with familial and sporadic melanoma (PMID:23787126;PMID:22080950). It affects a conserved residue and is predicted to be damaging by multiple in-silico tools (PP3). The variant is rare in population databases (PM2) and meets ACMG/AMP criteria for Pathogenic classification.

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 318 of the MITF protein (p.Glu318Lys). This variant is present in population databases (rs149617956, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with cutaneous melanoma (PMID: 22012259, 22080950, 23167872, 27473757). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 29792). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MITF protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MITF function (PMID: 22012259, 22080950, 23787126). For these reasons, this variant has been classified as Pathogenic.

Comment:

NM_001354604.2(MITF):c.1273G>A (p.Glu425Lys) is a missense variant that results in the substitution of glutamic acid with lysine. Segregation evidence has been reported in affected families. Functional evidence supports a deleterious effect on the gene or gene product (PMID: 22012259; PMID: 22080950; PMID: 23167872; PMID: 27473757; PMID: 23787126). This variant has been recurrently observed in individuals with related phenotype (PMID: 22012259; PMID: 22080950; PMID: 23167872; PMID: 27473757; PMID: 23787126). Based on the available data, this variant is classified as pathogenic.

Comment:

PS3_Moderate: Well-established in vitro and in vivo functional studies supportive of damaging effect on the gene product, with low residual enzymatic activity relative to wild-type reported (PMID: 22012259, 22080950, 23787126, 28376192); PS4: Prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls: one case-control studies investigating MITF missense mutations indicate this mutation has an OR > 2, with valid confidence intervals and p-values < 0.005 (PMID: 22012259, 22080950, 26775776, 27473757); PM2: Maximum gnomAD MAF of 0.246% in European-Non Finnish (NFE) subpopulation (<0.246% threshold); PP1: Cosegregation with melanoma across multiple affected family members in over 10 unrelated families (PMID: 22012259, 22080950); PP4: Variant reported in patients with highly specific phenotype for disease fitting (PMID: 22012259, 22080950, 27473757, 30414346)

Comment:

Published functional studies demonstrate a damaging effect: impaired sumoylation and differentially regulated expression of several MITF target genes (Bertolotto 2011, Yokoyama 2011, Grill 2013, Bonet 2017); Most case control studies suggest variant is associated with melanoma (OR=2.09-4.78), with an enrichment of the variant in patients with multiple primary melanomas and those with a family history of melanoma (Bertolotto 2011, Yokoyama 2011, Ghiorzo 2013, Gromowski 2014, Wadt 2015, Potrony 2016); Overrepresented among renal cell carcinoma cases (OR=5.19) and in individuals diagnosed with both melanoma and renal cell carcinoma (OR=14.46) (Bertolotto 2011); This variant is associated with the following publications: (PMID: 23787126, 27473757, 28125078, 28825054, 31034483, 22012259, 22080950, 28376192, 23167872, 24767713, 25803691, 26650189, 23774529, 24406078, 27153395, 27680874, 26800492, 27181379, 26775776, 26999813, 26999650, 27899189, 27720647, 28787086, 28152038, 24660985, 24290354, 23802662, 23046018, 22158021, 2440678, 24352080, 29485552, 29706638, 29506128, 30759220, 31201024, 30414346, 32054529, 31465090, 33240314)

Comment:

This variant is a recurrent alteration that has been reported as a heterozygous change in multiple individuals with cutaneous melanoma, renal cell carcinoma, or both cancers (PMID: 22012259, 22012259, 22080950, 27473757). A large case-controlled study observed that individuals with the p.Glu419Lys variant had a significantly increased risk of cutaneous melanoma (PMID: 22080950). Additionally, several studies showed the p.Glu419Lys variant had moderate co-segregation with melanoma, supporting the theory that this variant is a moderate penetrance melanoma risk factor (PMID: 22080950, 22012259, 23167872). Experimental studies have shown that the p.Glu419Lys variant leads to abnormal transcription of target genes and, in certain cell lines, increased colony forming potential (PMID: 22012259, 22080950, 23787126). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.1% (386/282776). In silico tools used to predict the effect of this variant on protein function yield discordant results. Based on the available evidence, the c.1255G>A (p.Glu419Lys) variant is classified as Pathogenic.

Comment:

The MITF c.952G>A; p.Glu318Lys variant (rs149617956, ClinVar variation ID: 29792) is reported in the literature in patients affected with renal cell carcinoma and sporadic and familial melanoma (Bertolotto 2011, Yokoyama 2011, Backman 2021, Bonet 2017). This variant is found in the general population with an overall allele frequency of 0.14% (386/282776 alleles) in the Genome Aggregation Database (v2.1.1). In vitro and in vivo functional analyses demonstrate the glutamic acid to lysine amino acid change results in defective SUMOylation of the MITF protein causing defective cellular senescence (Bertolotto 2011, Bonet 2017). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.438). Based on available information, this variant is considered to be pathogenic. References: Bertolotto, C et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature 480, 94-98 (2011). PMID: 22012259 Yokoyama S et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011;480(7375):99-103. Published 2011 Nov 13. PMID: 22080950 Backman JD et al. Exome sequencing and analysis of 454,787 UK Biobank participants. Nature. 2021;599(7886):628-634. PMID: 34662886 Bonet C et al. Deciphering the Role of Oncogenic MITFE318K in Senescence Delay and Melanoma Progression. J Natl Cancer Inst. 2017;109(8). PMID: 28376192

Comment:

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.

Comment:

Variant summary: Variant summary: 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. Three 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 262840 control chromosomes. This frequency is not higher than the estimated maximum 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 (e.g. Bertolotto_2011, Yokoyama_2012, Ghiorzo_2012, Potjer_2018), where the variant was noted to segregate with the disease in some, but not all families, indicating that the E318K is a possible intermediate risk variant. In a large case-control study authors observed that 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). The variant was also observed in individuals with personal and/or family history of breast cancer and other tumor phenotypes (Oliveira_2021), however a meta-analysis found minimal evidence for E318K's contribution to non-melanoma cancer risk (Guhan_2020). Experimental evidence suggests that this missense change causes decreased SUMOylation of MITF, resulting in an increased transcriptional activity with enhanced 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 had promoter specific effects on transcription of its target genes (Grill_2013). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=9) / likely pathogenic (n=3) or as a risk factor (n=2). Based on the 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 pathogenic.

Comment:

PS4, PP1_VeryStrong c.952G>A, located in exon 9 of the MITF gene, is predicted to result in the substitution of glutamic acid by lysine at codon 318, p.(Glu318Lys). This variant is found in 346/268238 alleles at a frequency of 0.13% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.438) is undetermined regarding the effect that it may have on protein function according to Pejaver 2022 thresholds (PMID:36413997). Functional analyses of p.E318K have shown that it impairs sumoylation and alters MITF transcriptional activity in transfected melanoma cell lines (PMID: 22080950, 22012259, 23787126). Several case-control studies have confirmed an association between this mutation and the risk of melanoma and or renal cell carncinoma (OR=2.19 [95% CI 1.41-3.45 P=0,0003] PMID:22080950, OR=4,78 [95% CI 2,05-11,75 p<0,0001] PMID: 22012259, OR=1.7 [95% CI 1.1-2.7 p=0,03] PMID: 24406078, OR=2.85 [95% CI 1.31-6.18 p=0.011] PMID: 23167872, OR=3,3 [95% CI 1.43-7,42 P<0,01] PMID: 26650189, OR = 3,16 PMID: 25803691) (PS4). This variant cosegregates in multiple melanoma families with a LOD score: 2,7, equivalent to LR:501 (PMID:22080950) (PP1_veryStrong). This variant has been reported in the ClinVar database (17x pathogenic, 7x likely pathogenic), in the LOVD database (1x pathogenic). Based on currently available information, the variant c.952G>A should be considered a pathogenic variant according to ACMG/AMP classification guidelines.

Comment:

The MITF c.952G>A (p.Glu318Lys) variant has been reported in the published literature in multiple individuals with melanoma and/or renal cell carcinoma (PMID: 22012259 (2011), 22080950 (2011), 24638154 (2014), 26775776 (2016), 26800492 (2016), 27473757 (2016), 30414346 (2019), 32054529 (2020), 35441217 (2022), 36863448 (2023), 37635363 (2024), 37864521 (2024), 39089886 (2024), 39315505 (2025)), and multiple case-control studies have shown that this variant is associated with an increased risk for melanoma and/or renal cell carcinoma (PMID: 22012259 (2011), 22080950 (2011), 23167872 (2013), 25803691 (2015), 26650189 (2016)). In addition, functional studies have shown that this variant causes MITF protein overactivity (PMID: 22012259 (2011), 22080950 (2011), 23787126 (2013)). Based on the available information, this variant is classified as pathogenic.

Comment:

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. 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, 28376192). This variant has been reported in multiple individuals affected with cutaneous melanoma (PMID: 22012259, 22080950, 23774529, 24638154, 24660985, 25943250, 26103950, 26775776, 26800492, 27473757, 30414346), Ewing sarcoma (PMID: 28125078), pheochromocytomas/paragangliomas (PMID: 27680874), and renal cell carcinoma (PMID: 22012259). Multiple large case-control studies have shown that this variant is associated with an increased risk of melanoma (OR 1.7-5.5PMID: 22012259, 22080950, 25803691, 26650189, 26775776). 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). Based on the available evidence, this variant is considered a lower penetrance risk allele and is classified as Likely Pathogenic.

Comment:

The missense variant (chr3:69964940 G>A), located in exon 9 (of 9), is reported in ClinVar (VCV000029792.116) and gnomAD v4.1 non-UKB with an allele frequency of 0.16%, and described in the scientific literature in patients with melanoma and pancreatic cancer (PMID: 22012259, 22080950, 23787126, 23167872, 27473757, 29506128, 23167872). In silico analysis is inconclusive regarding the impact of this variant; however, functional studies suggest that this variant affects protein function (PMID: 22012259, 22080950, 23787126). Based on the currently available evidence, this variant has been classified as likely pathogenic (PS3_P, PS4, PP1).

Comment:

This variant results in a c.952G>A (p.Glu318Lys) and a c.1255G>A (p.Glu419Lys) change in alternate transcripts (NM_000248.4, NM_198159.2). The c.1273G>A (p.Glu425Lys) variant affects a highly conserved amino acid; however, in silico tools used to predict the effect of this variant on protein function yield discordant results. This is a recurrent variant that has been reported as a heterozygous change in individuals with cutaneous melanoma and/or renal cell carcinoma (PMID: 22012259, 22080950, 27473757). A large case-controlled study involving approximately 4,000 participants observed that individuals with the c.1273G>A (p.Glu425Lys) variant had a significantly increased risk of cutaneous melanoma (OR=2.19 CI: 1.41-3.45) (PMID: 22080950). Additionally, several studies of families harboring this variant showed moderate co-segregation with melanoma (LOD = 2.7), providing evidence to support c.1273G>A (p.Glu425Lys) as an intermediate penetrance melanoma risk variant (PMID: 22080950, 22012259, 23167872). Experimental studies have shown that this missense change decreases the SUMOylation of MITF, leading to elevated transcription of target genes and increased colony forming potential in certain cell lines (PMID: 22012259, 22080950, 23787126). The c.1273G>A (p.Glu425Lys) variant is present in the latest version of the gnomAD population database at an allele frequency of 0.3% (4491/1614114), including 10 homozygotes. Based on the available evidence, c.1273G>A (p.Glu425Lys) is classified as Pathogenic.

Comment:

Variant interpreted as Pathogenic and reported on 10-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Comment:

Variant identified in multiple registry participants. Variant interpreted as Likely pathogenic and reported on 01-03-2018 by Lab or GTR ID 505849 an interpreted as Pathogenic and reported on 09-18-2017 by Lab or GTR ID 61756. 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic insights into Tietz albinism-deafness syndrome: A new dominant-negative mutation in MITF.	Yamamoto K	Pigment cell & melanoma research	2024	PMID: 38439523
MITF E318K: A rare homozygous case with multiple primary melanoma.	Wallingford CK	Pigment cell & melanoma research	2024	PMID: 37635363
Germline Variants in Childhood Cutaneous Melanoma.	Johansson PA	The Journal of investigative dermatology	2023	PMID: 36863448
Exome sequencing and analysis of 454,787 UK Biobank participants.	Backman JD	Nature	2021	PMID: 34662886
Expanding the phenotype of E318K (c.952G > A) MITF germline mutation carriers: case series and review of the literature.	Oliveira LJC	Hereditary cancer in clinical practice	2021	PMID: 34289891
Identification of Novel BRCA1 and RAD50 Mutations Associated With Breast Cancer Predisposition in Tunisian Patients.	Mighri N	Frontiers in genetics	2020	PMID: 33240314
Cancer risks associated with the germline MITF(E318K) variant.	Guhan SM	Scientific reports	2020	PMID: 33051548
Clinical, pathological and dermoscopic phenotype of MITF p.E318K carrier cutaneous melanoma patients.	Ciccarese G	Journal of translational medicine	2020	PMID: 32054529
Pathogenic Germline Variants in Patients With Metastatic Breast Cancer.	Stuttgen K	JAMA oncology	2019	PMID: 31465090
Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non-CDKN2A/CDK4 melanoma families.	Potjer TP	International journal of cancer	2019	PMID: 30414346
Genome-wide linkage analysis in Spanish melanoma-prone families identifies a new familial melanoma susceptibility locus at 11q.	Potrony M	European journal of human genetics : EJHG	2018	PMID: 29706638
Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms.	Lowery MA	Journal of the National Cancer Institute	2018	PMID: 29506128
Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making.	Abida W	JCO precision oncology	2017	PMID: 28825054
Deciphering the Role of Oncogenic MITFE318K in Senescence Delay and Melanoma Progression.	Bonet C	Journal of the National Cancer Institute	2017	PMID: 28376192
Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels.	LaDuca H	PloS one	2017	PMID: 28152038
Frequent inactivating germline mutations in DNA repair genes in patients with Ewing sarcoma.	Brohl AS	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28125078
Biallelic Mutations in MITF Cause Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness.	George A	American journal of human genetics	2016	PMID: 27889061
The MITF, p.E318K Variant, as a Risk Factor for Pheochromocytoma and Paraganglioma.	Castro-Vega LJ	The Journal of clinical endocrinology and metabolism	2016	PMID: 27680874
Genetic susceptibility to cutaneous melanoma in southern Switzerland: role of CDKN2A, MC1R and MITF.	Mangas C	The British journal of dermatology	2016	PMID: 27473757
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
The Microphthalmia-Associated Transcription Factor p.E318K Mutation Does Not Play a Major Role in Sporadic Renal Cell Tumors from Caucasian Patients.	Stoehr CG	Pathobiology : journal of immunopathology, molecular and cellular biology	2016	PMID: 26999813
Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome.	Soura E	Journal of the American Academy of Dermatology	2016	PMID: 26892650
Characterization of patients at high risk of melanoma in Austria.	Müller C	The British journal of dermatology	2016	PMID: 26800492
Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup.	Bruno W	Journal of the American Academy of Dermatology	2016	PMID: 26775776
Prevalence of MITF p.E318K in Patients With Melanoma Independent of the Presence of CDKN2A Causative Mutations.	Potrony M	JAMA dermatology	2016	PMID: 26650189
High incidence of primary melanomas in an MC1R RHC homozygote/CDKN2A mutant genotype patient.	Sinnya S	Archives of dermatological research	2015	PMID: 26103950
The lack of E318K MITF germline mutation in Latvian melanoma patients.	Ozola A	Cancer genetics	2015	PMID: 25975176
CDKN2a mutation-negative melanoma families have increased risk exclusively for skin cancers but not for other malignancies.	Helgadottir H	International journal of cancer	2015	PMID: 25943250
Molecular characterization of melanoma cases in Denmark suspected of genetic predisposition.	Wadt KA	PloS one	2015	PMID: 25803691
MITF in melanoma: mechanisms behind its expression and activity.	Hartman ML	Cellular and molecular life sciences : CMLS	2015	PMID: 25433395
Updated field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma: the MelGene database.	Antonopoulou K	The Journal of investigative dermatology	2015	PMID: 25407435
Prevalence of the E318K and V320I MITF germline mutations in Polish cancer patients and multiorgan cancer risk-a population-based study.	Gromowski T	Cancer genetics	2014	PMID: 24767713
Genotype analysis in Hungarian patients with multiple primary melanoma.	Hatvani Z	Experimental dermatology	2014	PMID: 24660985
Multiple primary melanomas versus single melanoma of the head and neck: a comparison of genetic, diagnostic, and therapeutic implications.	Pollio A	Melanoma research	2014	PMID: 24638154
MITF E318K's effect on melanoma risk independent of, but modified by, other risk factors.	Berwick M	Pigment cell & melanoma research	2014	PMID: 24406078
The impact of MITF on melanoma development: news from bench and bedside.	Roider EM	The Journal of investigative dermatology	2014	PMID: 24352080
A germline oncogenic MITF mutation and tumor susceptibility.	Paillerets BB	European journal of cell biology	2014	PMID: 24290354
Phenotypic characterization of nevus and tumor patterns in MITF E318K mutation carrier melanoma patients.	Sturm RA	The Journal of investigative dermatology	2014	PMID: 23774529
Malignant and benign tumors associated with multiple primary melanomas: just the starting block for the involvement of MITF, PTEN and CDKN2A in multiple cancerogenesis?	Pollio A	Pigment cell & melanoma research	2013	PMID: 23802662
MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function.	Grill C	Human molecular genetics	2013	PMID: 23787126
Prevalence of the E318K MITF germline mutation in Italian melanoma patients: associations with histological subtypes and family cancer history.	Ghiorzo P	Pigment cell & melanoma research	2013	PMID: 23167872
Cancer genomics: Finding a rare variant.	Seton-Rogers S	Nature reviews. Cancer	2011	PMID: 22158021
A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma.	Yokoyama S	Nature	2011	PMID: 22080950
A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.	Bertolotto C	Nature	2011	PMID: 22012259
Review and update of mutations causing Waardenburg syndrome.	Pingault V	Human mutation	2010	PMID: 20127975
Tietz syndrome: unique phenotype specific to mutations of MITF nuclear localization signal.	Izumi K	Clinical genetics	2008	PMID: 18510545
Molecular cloning of cDNA encoding a novel microphthalmia-associated transcription factor isoform with a distinct amino-terminus.	Fuse N	Journal of biochemistry	1999	PMID: 10578055
Waardenburg syndrome.	Read AP	Journal of medical genetics	1997	PMID: 9279758
Apparent digenic inheritance of Waardenburg syndrome type 2 (WS2) and autosomal recessive ocular albinism (AROA).	Morell R	Human molecular genetics	1997	PMID: 9158138
Conformation of cytoplasmic segments of acetylcholine receptor alpha- and beta-subunits probed by monoclonal antibodies: sensitivity of the antibody competition approach.	Kordossi AA	The EMBO journal	1987	PMID: 2440678
Heterogeneity in Waardenburg's syndrome. Report of a family with ocular albinism.	Bard LA	Archives of ophthalmology (Chicago, Ill. : 1960)	1978	PMID: 666627
https://spadahc.ciberisciii.es/variant/GRCH37/3%2070014091%20G/A	-	-	-	-
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Text-mined citations for rs149617956 ...

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Record last updated Jul 27, 2026