Submissions for variant NM_000264.5(PTCH1):c.3376G>A (p.Val1126Ile)

gnomAD frequency: 0.00012  dbSNP: rs147025073

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001085114	SCV000218544	benign	Gorlin syndrome	2024-01-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575313	SCV000674545	likely benign	Hereditary cancer-predisposing syndrome	2020-05-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000167898	SCV001155670	likely benign	not provided	2018-02-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000167898	SCV002009310	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121891	SCV002014859	likely benign	not specified	2021-10-11	criteria provided, single submitter	clinical testing	Variant summary: PTCH1 c.3376G>A (p.Val1126Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 251250 control chromosomes, predominantly at a frequency of 0.00049 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 29 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTCH1 causing Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) phenotype (1.7e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3376G>A has been reported in the literature in individuals affected Pancreatic ductal adenocarcinoma or Ovarian cancer (example, Lovecek_2019 and Li_2019). Co-occurrences with other pathogenic variant have been reported in at least one individual, providing supporting evidence for a benign role for this variant (Li_PTC1_PNAS_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and have classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000575313	SCV002526888	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-07	criteria provided, single submitter	curation
GeneDx	RCV000167898	SCV002765884	likely benign	not provided	2019-03-22	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000167898	SCV004219216	likely benign	not provided	2022-09-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952612	SCV004785546	likely benign	PTCH1-related condition	2022-03-10	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).
ITMI	RCV000121891	SCV000086094	not provided	not specified	2013-09-19	no assertion provided	reference population