Submissions for variant NM_000264.5(PTCH1):c.2270T>C (p.Phe757Ser)

gnomAD frequency: 0.00001  dbSNP: rs547954117

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231046	SCV000284327	likely benign	Gorlin syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000231046	SCV000481302	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	RCV000302132	SCV000481303	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000231046	SCV000891000	likely benign	Gorlin syndrome	2020-08-19	criteria provided, single submitter	clinical testing	The c.2270T>C (p.Phe757Ser) missense variant has a frequency of 0.0003504 (88 of 251,124 alleles) in gnomAD v2.1.1 with a maximum allele frequency of 0.002744 (84 of 30,614) in the South Asian population (http://gnomad.broadinstitute.org). This exceeds the expected incidence of a pathogenic variant causing Gorlin syndrome, in which the prevalence is estimated to be 1 in 31,000 people (0.003%) (BS1). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), however this has not been confirmed in functional assays. To our knowledge, this variant has not been reported in individuals with Gorlin syndrome (internal data and literature review). In summary, this variant meets criteria to be classified as likely benign as the population frequency is not consistent with disease. ACMG/AMP criteria met: BS1, PP3.
Ambry Genetics	RCV001015005	SCV001175788	benign	Hereditary cancer-predisposing syndrome	2020-12-28	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.
CeGaT Center for Human Genetics Tuebingen	RCV003430777	SCV004160202	benign	not provided	2022-08-01	criteria provided, single submitter	clinical testing	PTCH1: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV003955303	SCV004768477	likely benign	PTCH1-related condition	2019-04-18	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).