ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs547954117
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Total submissions: 7
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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: 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 RCV003430777 SCV004160202 benign not provided 2022-08-01 criteria provided, single submitter clinical testing PTCH1: BS1, BS2
PreventionGenetics, part of Exact Sciences RCV004547584 SCV004768477 likely benign PTCH1-related disorder 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).

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