NM_000264.5(PTCH1):c.2270T>C (p.Phe757Ser) AND Gorlin syndrome

Clinical significance:Benign/Likely benign (Last evaluated: Dec 3, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000231046.10

Allele description [Variation Report for NM_000264.5(PTCH1):c.2270T>C (p.Phe757Ser)]

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

Genes:
PTCH1:patched 1 [Gene - OMIM - HGNC]
LOC100507346:uncharacterized LOC100507346 [Gene]
Variant type:
single nucleotide variant
Cytogenetic location:
9q22.32
Genomic location:
Preferred name:
NM_000264.5(PTCH1):c.2270T>C (p.Phe757Ser)
HGVS:
  • NC_000009.12:g.95467406A>G
  • NG_007664.1:g.54560T>C
  • NM_000264.5:c.2270T>CMANE SELECT
  • NM_001083602.2:c.2072T>C
  • NM_001083603.2:c.2267T>C
  • NM_001083604.2:c.1817T>C
  • NM_001083605.2:c.1817T>C
  • NM_001083606.3:c.1817T>C
  • NM_001083607.2:c.1817T>C
  • NM_001354918.2:c.2114T>C
  • NP_000255.2:p.Phe757Ser
  • NP_001077071.1:p.Phe691Ser
  • NP_001077072.1:p.Phe756Ser
  • NP_001077073.1:p.Phe606Ser
  • NP_001077074.1:p.Phe606Ser
  • NP_001077075.1:p.Phe606Ser
  • NP_001077076.1:p.Phe606Ser
  • NP_001341847.1:p.Phe705Ser
  • LRG_515t1:c.2270T>C
  • LRG_515:g.54560T>C
  • NC_000009.11:g.98229688A>G
  • NM_000264.3:c.2270T>C
  • NR_038982.1:n.556A>G
Protein change:
F606S
Links:
dbSNP: rs547954117
NCBI 1000 Genomes Browser:
rs547954117
Molecular consequence:
  • NM_000264.5:c.2270T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001083602.2:c.2072T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001083603.2:c.2267T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001083604.2:c.1817T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001083605.2:c.1817T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001083606.3:c.1817T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001083607.2:c.1817T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354918.2:c.2114T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_038982.1:n.556A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Gorlin syndrome (BCNS)
Synonyms:
Gorlin-Goltz Syndrome; Multiple Basal Cell Nevi, Odontogenic Keratocysts, And Skeletal Anomalies; Fifth Phacomatosis; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007187; MedGen: C0004779; Orphanet: 377; OMIM: 109400

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000284327Invitaecriteria provided, single submitter
Likely benign
(Dec 3, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000481302Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Benign
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV000891000St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospitalcriteria provided, single submitter
Likely benign
(Aug 19, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000284327.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Illumina Clinical Services Laboratory,Illumina, SCV000481302.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital, SCV000891000.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 6, 2021

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