Submissions for variant NM_000264.5(PTCH1):c.37C>G (p.Arg13Gly)

gnomAD frequency: 0.00063  dbSNP: rs779791579

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168136	SCV000218796	benign	Gorlin syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000388546	SCV000481356	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000168136	SCV000481357	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000512831	SCV000609345	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PTCH1: BS1
Ambry Genetics	RCV000567817	SCV000674455	likely benign	Hereditary cancer-predisposing syndrome	2019-07-01	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.
Fulgent Genetics, Fulgent Genetics	RCV000764853	SCV000896009	uncertain significance	Basal cell carcinoma, susceptibility to, 1; Gorlin syndrome; Holoprosencephaly 7	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000512831	SCV001786291	uncertain significance	not provided	2021-11-02	criteria provided, single submitter	clinical testing	Reported previously in an individual with breast cancer (Chan et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30093976)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000512831	SCV002011170	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000567817	SCV002526915	benign	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000512831	SCV004219230	likely benign	not provided	2022-10-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689645	SCV005185777	uncertain significance	not specified	2024-05-30	criteria provided, single submitter	clinical testing	Variant summary: PTCH1 c.37C>G (p.Arg13Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 8920 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.37C>G has been reported in the literature in one individual affected with Breast Cancer (Chan_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30093976). ClinVar contains an entry for this variant (Variation ID: 188208). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004552936	SCV004761010	likely benign	PTCH1-related disorder	2024-01-29	no assertion criteria provided	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).