ClinVar Miner

Submissions for variant NM_003738.5(PTCH2):c.3347C>T (p.Pro1116Leu) (rs539161089)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000545138 SCV000623086 uncertain significance Gorlin syndrome 2017-08-07 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1116 of the PTCH2 protein (p.Pro1116Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs539161089, ExAC 0.01%). This variant has not been reported in the literature in individuals with PTCH2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics,Fulgent Genetics RCV000765169 SCV000896402 uncertain significance Basal cell carcinoma, multiple; 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).

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