Submissions for variant NM_000264.5(PTCH1):c.1686C>T (p.Ala562=)

gnomAD frequency: 0.15395  dbSNP: rs2066836

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000250191	SCV000303328	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000342546	SCV000481318	benign	Gorlin syndrome	2018-01-12	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	RCV000376238	SCV000481319	benign	Holoprosencephaly 7	2018-01-12	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.
Ambry Genetics	RCV000492508	SCV000581012	benign	Hereditary cancer-predisposing syndrome	2014-12-03	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Invitae	RCV000342546	SCV000622927	benign	Gorlin syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589282	SCV000696372	benign	not provided	2016-05-24	criteria provided, single submitter	clinical testing	Variant summary: The PTCH1 c.1686C>T (p.Ala562Ala) variant causes a synonymous change involving a non-conserved nucleotide with 4/5 splice prediction tools predicting no significant impact on splicing or ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 20642/118716 (2070 homozygotes, 1/5, frequency: 0.1738772), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PTCH1 variant of 1/58479 (0.0000171), suggesting this variant is likely a benign polymorphism. In addition, the variant has been indicated to co-occur with other pathogenic PTCH1 variants, c.2011_2012dup and c.3050_3051del, in affected individuals via publications. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589282	SCV000884423	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000589282	SCV001942753	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000342546	SCV004017129	benign	Gorlin syndrome	2023-07-07	criteria provided, single submitter	clinical testing