Submissions for variant NM_001354604.2(MITF):c.1213T>C (p.Ser405Pro)

gnomAD frequency: 0.00004  dbSNP: rs104893747

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001541066	SCV001759020	uncertain significance	not provided	2024-06-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate conflicting results with respect to effect on DNA binding and phosphorylation abilities (PMID: 10587587, 23787126); Observed in individuals with melanoma or other cancers (PMID: 29625052); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28690485, 10587587, 10952390, 11764295, 23787126, 23098757, 29115496, 31589614, 36451132, 29625052, 8589691)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281708	SCV002572313	uncertain significance	not specified	2022-08-25	criteria provided, single submitter	clinical testing	Variant summary: MITF c.892T>C (p.Ser298Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251382 control chromosomes (gnomAD). c.892T>C has been reported in the literature as a heterozygous genotype in at least one affected individual from a family with a multi-generational history of Waardenburg Syndrome 2 (e.g. Tassabehji_1995) and has also been reported as a VUS in individuals with melanoma and head and neck squamous cell carcinoma (e.g. Huang_2018). These data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function, however with conflicting results. While the variant has been reported to impair DNA-binding and transactivational activity in one study (Takeda_2000), a different study found the variant protein had no effect on DNA-binding and resulted in mildly increased transcriptional activity at some promoters (Grill_2013). One clinical diagnostic laboratory has submitted a clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513060	SCV003513183	uncertain significance	Tietz syndrome; Waardenburg syndrome type 2A; Melanoma, cutaneous malignant, susceptibility to, 8	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 298 of the MITF protein (p.Ser298Pro). This variant is present in population databases (rs104893747, gnomAD 0.007%). This missense change has been observed in individual(s) with cutaneous melanoma and/or Waardenburg syndrome, type 2 (PMID: 8589691, 29115496, 29625052, 36451132). ClinVar contains an entry for this variant (Variation ID: 14277). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on MITF function (PMID: 10587587, 23787126). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004786263	SCV005402182	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 8	2024-01-21	criteria provided, single submitter	clinical testing	The MITF c.1195T>C (p.Ser399Pro) missense change has a maximum subpopulation frequency of 0.0054% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The variant is also known as NM_000248.4:c.892T>C;p.Ser298Pro. The in silico tool REVEL predicts a benign effect on protein function. Functional studies have yielded conflicting results regarding the DNA-binding and/or transactivation ability of the protein (PMID: 10587587, 23787126). This variant has been reported in individuals with Waardenburg syndrome, skin cutaneous melanoma and head and neck squamous cell carcinoma (PMID: 10587587, 8589691, 29625052). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
OMIM	RCV000015347	SCV000035606	pathogenic	Waardenburg syndrome type 2A	2000-01-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003974827	SCV004788188	uncertain significance	MITF-related disorder	2024-02-23	no assertion criteria provided	clinical testing	The MITF c.892T>C variant is predicted to result in the amino acid substitution p.Ser298Pro. This variant has been reported to segregate with Type 2 Waardenburg syndrome in a multigenerational pedigree (Tassabehji et al. 1995. PubMed ID: 8589691). It has also been reported in an individual with head and neck squamous cell carcinoma and an individual with cutaneous melanoma (Huang et al. 2018. PubMed ID: 29625052, Table S2B, Chr3:g.70014031T>C). In vitro experimental studies provide conflicting results of this variants impact on protein function (Takeda et al. 2000. PubMed ID: 10587587; Grill et al. 2013. PubMed ID: 23787126). It is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/14277/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.