chr9-95480450-GGG-TAA

Variant names:

• chr9-95480450-GGG-TAA
• NM_000264.5:c.883_885delCCCinsTTA
• PTCH1 p.Pro295Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_000264.5(PTCH1):c.883_885delCCCinsTTA (p.Pro295Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.60). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P295L: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 135908); p.P295= (synonymous): Likely_benign (ClinVar VariationId 1764907, 1 star); p.P295= (synonymous): Likely_benign (ClinVar VariationId 2916215, 2 stars); p.P295S: Uncertain_significance (ClinVar VariationId 2633768, 2 stars); p.P295T: Uncertain_significance (ClinVar VariationId 4862716, 1 star)

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

Genes affected

PTCH1 (HGNC:9585): (patched 1) This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]

PTCH1 Gene-Disease associations (from GenCC):

• basal cell nevus syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
• holoprosencephaly 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen
• exstrophy-epispadias complex

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina, ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000264.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PTCH1 NM_000264.5	MANE Select	c.883_885delCCCinsTTA p.Pro295Leu	missense	N/A	Prot: NP_000255.2 UniProt:
	PTCH1 NM_001083603.3	MANE Plus Clinical	c.880_882delCCCinsTTA p.Pro294Leu	missense	N/A	Prot: NP_001077072.1 UniProt:
	PTCH1 NM_001354918.2		c.883_885delCCCinsTTA p.Pro295Leu	missense	N/A	Prot: NP_001341847.1 UniProt:

PTCH1 NM_000264.5

MANE Select

HGVSc / HGVSpc.883_885delCCCinsTTAp.Pro295Leu

Exon rankN/A

missense

Prot: NP_000255.2UniProt: Q13635-1

PTCH1 NM_001083603.3

MANE Plus Clinical

HGVSc / HGVSpc.880_882delCCCinsTTAp.Pro294Leu

Exon rankN/A

missense

Prot: NP_001077072.1UniProt: Q13635-2

PTCH1 NM_001354918.2

HGVSc / HGVSpc.883_885delCCCinsTTAp.Pro295Leu

Exon rankN/A

missense

Prot: NP_001341847.1UniProt: A0A1W5YLI7

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PTCH1 ENST00000331920.11	TSL:5MANE Select	c.883_885delCCCinsTTA p.Pro295Leu	missense	N/A	Prot: ENSP00000332353.6 UniProt:
	PTCH1 ENST00000437951.6	TSL:5MANE Plus Clinical	c.880_882delCCCinsTTA p.Pro294Leu	missense	N/A	Prot: ENSP00000389744.2 UniProt:
	PTCH1 ENST00000429896.6	TSL:1	c.430_432delCCCinsTTA p.Pro144Leu	missense	N/A	Prot: ENSP00000414823.2 UniProt:

PTCH1 ENST00000331920.11

TSL:5MANE Select

HGVSc / HGVSpc.883_885delCCCinsTTAp.Pro295Leu

Exon rankN/A

missense

Prot: ENSP00000332353.6UniProt: Q13635-1

PTCH1 ENST00000437951.6

TSL:5MANE Plus Clinical

HGVSc / HGVSpc.880_882delCCCinsTTAp.Pro294Leu

Exon rankN/A

missense

Prot: ENSP00000389744.2UniProt: Q13635-2

PTCH1 ENST00000429896.6

TSL:1

HGVSc / HGVSpc.430_432delCCCinsTTAp.Pro144Leu

Exon rankN/A

missense

Prot: ENSP00000414823.2UniProt: Q13635-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.6

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr9-98242732;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar