ClinVar Miner

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

gnomAD frequency: 0.00012  dbSNP: rs147025073
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Total submissions: 10
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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: seen in unaffected individuals, 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 RCV004551190 SCV004785546 likely benign PTCH1-related disorder 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

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