Submissions for variant NM_001354604.2(MITF):c.1566G>A (p.Thr522=)

gnomAD frequency: 0.00991  dbSNP: rs36118030

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000220011	SCV000269240	benign	not specified	2014-11-24	criteria provided, single submitter	clinical testing	Thr516Thr in exon 10 of MITF: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 2.7% (120/4406) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs36118030).
Illumina Laboratory Services, Illumina	RCV000321130	SCV000445938	benign	Waardenburg syndrome type 2A	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000378135	SCV000445939	benign	Tietz syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587748	SCV000696085	benign	not provided	2016-03-04	criteria provided, single submitter	clinical testing	Variant summary: MITF c.1245G>A affects a non-conserved nucleotide, resulting in a synonymous change. 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESEfinder predicts changes of binding motifs for RNA splicing enhancers. This variant was found in 323/120562 control chromosomes at a frequency of 0.0026791, predominalty observed in African subpopulation in ExAC with MAF of 0.031 with 8 homozygotes. These frequencies significantly exceed the maximal expected frequency of a pathogenic MITF allele (0.0000125), suggesting this variant is benign. This variant has not, to our knowledge, been reported in affected individuals via publications or clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as Benign.
GeneDx	RCV000220011	SCV000713874	benign	not specified	2018-02-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Athena Diagnostics	RCV000587748	SCV001144507	benign	not provided	2018-12-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002054376	SCV002393235	benign	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8	2025-02-03	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003316180	SCV004015853	benign	Melanoma, cutaneous malignant, susceptibility to, 8	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000587748	SCV005302360	benign	not provided		criteria provided, single submitter	not provided
Ambry Genetics	RCV004943778	SCV005444983	likely benign	Hereditary cancer-predisposing syndrome	2024-10-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV000220011	SCV003839717	benign	not specified	2022-05-12	no assertion criteria provided	clinical testing