3-69964940-G-A

Position:

• chr3-69964940-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 8P and 2B. PP5_Very_Strong BP4 BS1_Supporting

The NM_001354604.2(MITF):​c.1273G>A​(p.Glu425Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,614,114 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,risk factor (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (9 hom.)
• Consequence: MITF NM_001354604.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic; risk factor criteria provided, multiple submitters, no conflicts P:23 O:5
• Conservation: PhyloP100: 8.01

Genes affected

MITF (HGNC:7105): (melanocyte inducing transcription factor) The protein encoded by this gene is a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. The encoded protein regulates melanocyte development and is responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PP5: Variant 3-69964940-G-A is Pathogenic according to our data. Variant chr3-69964940-G-A is described in ClinVar as [Likely_pathogenic, risk_factor]. Clinvar id is 29792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69964940-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.034677655). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00158 (240/152232) while in subpopulation NFE AF= 0.00244 (166/68008). AF 95% confidence interval is 0.00214. There are 1 homozygotes in gnomad4. There are 96 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MITF	NM_001354604.2	c.1273G>A	p.Glu425Lys	missense_variant	10/10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4	c.952G>A	p.Glu318Lys	missense_variant	9/9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9	c.1273G>A	p.Glu425Lys	missense_variant	10/10	1	NM_001354604.2	ENSP00000295600	P4
MITF	ENST00000394351.9	c.952G>A	p.Glu318Lys	missense_variant	9/9	1	NM_000248.4	ENSP00000377880

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 240 AN: 152114 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00136 AC: 342 AN: 251388 Hom.: 0 AF XY: 0.00135 AC XY: 184 AN XY: 135858

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00249

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00291 AC: 4251 AN: 1461882 Hom.: 9 Cov.: 31 AF XY: 0.00273 AC XY: 1983 AN XY: 727244

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.00362

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152232 Hom.: 1 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74420

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00244

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00231 Hom.: 3

Bravo AF: 0.00179

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00133 AC: 161

EpiCase AF: 0.00278

EpiControl AF: 0.00261

ClinVar

Significance: Pathogenic/Likely pathogenic; risk factor

Submissions summary: Pathogenic:23 Other:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma, cutaneous malignant, susceptibility to, 8 Pathogenic:9 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 01, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PP1 moderated -
risk factor, no assertion criteria provided	literature only	OMIM	Nov 13, 2011	- -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 26, 2022	PS3_Moderate, PS4, PP1_Moderate, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Feb 17, 2023	ACMG Criteria: PS3, PS4, PP1, PP5; Variant was found in heterozygous state. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing;provider interpretation	Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	Jun 06, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 03, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jan 03, 2022	The MITF c.1255G>A (p.Glu419Lys) missense change has a maximum population frequency of 0.25% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is known in the literature as NM_000248.4: c.952G>A (p.Glu318Lys). It has been reported in individuals with melanoma (PMID: 22012259, 22080950, 23167872, 23774529, 25803691, 26650189, 27473757), where the variant has been shown to segregate with disease in studies of families with multiple instances of melanoma (PMID: 22012259, 22080950, 23167872). In addition, case-control studies have indicated that individuals with this variant had a significantly increased risk of developing melanoma with an odds ratio of greater than 2 (PMID: 22080950). This variant has also been observed in individuals with a personal and/or family history of renal cell carcinoma (PMID: 22012259, 23167872, 26650189). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, but functional studies have shown decreased SUMOlation of MITF leading to elevated transcription of target genes as compared to the wild-type protein (PMID: 22012259, 22080950, 23787126). In summary, this variant meets criteria to be classified as pathogenic. -

not provided Pathogenic:8 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	The MITF c.952G>A; p.Glu318Lys variant (rs149617956) 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 also reported in ClinVar (Variation ID: 29792) and is found in African, Latino, and European populations with an overall allele frequency of 0.14% (386/282776 alleles) in the Genome Aggregation Database. 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 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2020	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 16, 2021	In the published literature, this variant has been reported in multiple individuals with melanoma and/or renal cell carcinoma (PMIDs: 22012259 (2011), 22080950 (2011), 24638154 (2014), 26775776 (2016), 26800492 (2016), 27473757 (2016), 30414346 (2019), and 32054529 (2020)). Also, multiple case-control studies have shown that this variant is associated with an increased risk for melanoma and/or renal cell carcinoma (PMIDs: 22012259 (2011), 22080950 (2011), 23167872 (2013), 25803691 (2015), and 26650189 (2016)). In addition, functional studies have shown that this variant causes MITF protein overactivity (PMIDs: 22012259 (2011), 22080950 (2011), and 23787126 (2013)). Therefore, this variant is predicted to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Nov 02, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 30, 2022	PS3_supporting, PS4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	MITF: PS3, PM1, PP1, PS4:Supporting -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 23, 2021	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 available evidence, this alteration is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 17, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 05, 2023	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, 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), or renal cell carcinoma (PMID: 22012259). Multiple case-control studies have shown that this variant is associated with an increased risk of melanoma (PMID: 22012259, 22080950, 25803691, 26650189, 26775776). In addition, this variant is associated with an increased risk of renal cell carcinoma (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. -

Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

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 autosomal dominant 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -

Tietz syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8;C4310625:Coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2022

- -

not specified Other:1

risk factor, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

- -

Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

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. -

Melanoma Other:1

risk factor, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 04, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.035	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.018	D
MutationAssessor	Pathogenic	3.0	.;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N;N;.;N;N;N;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.039	D;D;.;D;T;D;D;D;D
Sift4G	Benign	0.081	T;T;.;T;T;T;T;T;T
Polyphen		0.98	D;.;D;.;D;D;D;D;.
Vest4		0.81
MVP		0.76
MPC		1.0
ClinPred		0.049	T
GERP RS		6.2
Varity_R		0.44
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149617956; hg19: chr3-70014091;