Submissions for variant NM_003738.5(PTCH2):c.3347C>T (p.Pro1116Leu)

gnomAD frequency: 0.00002  dbSNP: rs539161089

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545138	SCV000623086	uncertain significance	Gorlin syndrome	2023-03-24	criteria provided, single submitter	clinical testing	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. 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 expected to disrupt PTCH2 protein function. ClinVar contains an entry for this variant (Variation ID: 453938). This missense change has been observed in individual(s) with clinical features of PTCH2-related conditions (PMID: 31945512). This variant is present in population databases (rs539161089, gnomAD 0.006%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1116 of the PTCH2 protein (p.Pro1116Leu).
Fulgent Genetics, Fulgent Genetics	RCV000765169	SCV000896402	uncertain significance	Basal cell carcinoma, susceptibility to, 1; Gorlin syndrome; Medulloblastoma	2018-10-31	criteria provided, single submitter	clinical testing
Genetics, Children's Hospital New Orleans	RCV000545138	SCV000930016	uncertain significance	Gorlin syndrome	2019-07-29	criteria provided, single submitter	clinical testing	We report a male patient with a novel PTCH2 variant of uncertain significance inherited from the father. The proband displays several minor diagnostic findings observed in individuals with Gorlin syndrome, supporting the pathogenic role of this gene. Phenotypic features in the proband include macrocephaly, a wide face, prominent forehead, hypertelorism and telecanthus, large eyes, cleft lip and palate, thin vertical palmar creases, penoscrotal inversion, and a hyperpigmented spot on his penis. The father displays macrocephaly, several nevi on his back and shoulders, and a single palmar pit on his left hand, raising suspicion for Gorlin syndrome. PTCH2 encodes a transmembrane receptor of the patched gene family. It has been suggested that PTCH2 is a functional Sonic hedgehog receptor, and has tumor-suppressor function (Fan et al., 2008; MIM 603673; Zhulyn et al., 2015). A heterozygous missense variant in PTCH2 has been reported in one family in association with nevoid basal cell carcinoma syndrome (NBCCS) (Fan et al., 2008). Another patient with NBCCS was found to have a frameshift variant resulting in truncation of the PTCH2 protein and haploinsufficiency (Fujii et al., 2013). NBCCS is an autosomal dominant condition characterized by lamellar calcification of the falx, jaw keratocyst, palmar/plantar pits, and multiple basal cell carcinomas in addition to skeletal anomalies, macrocephaly, oral clefting, ovarian/cardiac fibroma, lymphomesenteric cysts and ocular abnormalities; however, intra- and interfamilial variability has been observed (Evans and Farndon, 2013; Bree et al., 2011). This semi-conservative amino acid substitution has not been reported in the literature as either a benign or pathogenic variant. Two entries exist within a whole exome sequencing healthy population reference database for this missense variant, once in an individual of East Asian decent and once in an individual of European non-Finnish descent, suggesting an allele frequency of 0.000008076 (gnomAD), raising the possibility of a rare benign variant. Other variants at this codon have been reported as well in healthy reference populations, again raising concerns that observed variant is rare and benign. While Gorlin syndrome displays complete penetrance when attributed to PTCH1 variants, several reported pathogenic PTCH2 variants have been identified in individuals with features of NBCCs as well as apparently healthy reference populations, suggesting incomplete penetrance in PTCH2-related disease (Fujii et al. 2013; Fan et al., 2008). A recent case report by Altaraihi et al. describes a homozygous mother and heterozygous daughter with a frameshift mutation in PTCH2. Although both patients display significant pathology, neither exhibit features characteristic of NBCCS, further challenging the pathogenicity of this gene in the context of Gorlin syndrome (Altaraihi et al. 2019). Available in silico analysis produces inconsistent, contradictory predictions regarding impact of this amino acid substitution on PTCH2 protein structure and function (Polyphen 2: benign, score 0.319; SIFT: Damaging; MutTaster: disease causing, score 0.999). Additional in silico modeling suggests that this variant may result in altered splicing or exon skipping (HSP3.1; Ex-Skip).
PreventionGenetics, part of Exact Sciences	RCV004737603	SCV005353464	uncertain significance	PTCH2-related disorder	2024-08-05	no assertion criteria provided	clinical testing	The PTCH2 c.3347C>T variant is predicted to result in the amino acid substitution p.Pro1116Leu. This variant was reported in the heterozygous state in three family members with minor diagnostic features of a Gorlin syndrome-like phenotype (nevoid basal-cell carcinoma syndrome); however all three family members do not meet clinical criteria for Gorlin syndrome (Casano et al. 2020. PubMed ID: 31945512). This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD and is classified as a variant of uncertain significance in gnomAD (https://www.ncbi.nlm.nih.gov/clinvar/variation/453938/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.