ClinVar Miner

Submissions for variant NM_000264.5(PTCH1):c.2270T>C (p.Phe757Ser) (rs547954117)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231046 SCV000284327 likely benign Gorlin syndrome 2020-12-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,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 Clinical Genomics Lab, 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 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-07 criteria provided, single submitter clinical testing The p.F757S variant (also known as c.2270T>C), located in coding exon 15 of the PTCH1 gene, results from a T to C substitution at nucleotide position 2270. The phenylalanine at codon 757 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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