9-95467118-T-G

Variant names:

• chr9-95467118-T-G
• rs587778628
• NM_000264.5:c.2558A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000264.5(PTCH1):​c.2558A>C​(p.Gln853Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q853R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH1 NM_000264.5 missense, splice_region
• Scores: Splicing: ADA: 0.007144
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.83
• Publications: 2 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 Submitted by: G2P
• holoprosencephaly 7

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

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

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

LOC100507346 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• PP5: Variant 9-95467118-T-G is Pathogenic according to our data. Variant chr9-95467118-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 428818.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	NM_000264.5	MANE Select	c.2558A>C	p.Gln853Pro	missense splice_region	Exon 15 of 24	NP_000255.2
	PTCH1	NM_001083603.3	MANE Plus Clinical	c.2555A>C	p.Gln852Pro	missense splice_region	Exon 15 of 24	NP_001077072.1
	PTCH1	NM_001354918.2		c.2402A>C	p.Gln801Pro	missense splice_region	Exon 14 of 23	NP_001341847.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTCH1	ENST00000331920.11	TSL:5 MANE Select	c.2558A>C	p.Gln853Pro	missense splice_region	Exon 15 of 24	ENSP00000332353.6
	PTCH1	ENST00000437951.6	TSL:5 MANE Plus Clinical	c.2555A>C	p.Gln852Pro	missense splice_region	Exon 15 of 24	ENSP00000389744.2
	PTCH1	ENST00000429896.6	TSL:1	c.2105A>C	p.Gln702Pro	missense splice_region	Exon 15 of 24	ENSP00000414823.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 10, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q853P variant (also known as c.2558A>C), located in coding exon 15 of the PTCH1 gene, results from an A to C substitution at nucleotide position 2558. The glutamine at codon 853 is replaced by proline, an amino acid with similar properties. This variant was reported in individuals with features consistent with PTCH1-related nevoid basal cell carcinoma syndrome (Ambry internal data, external communication); in at least one individual, it was determined to be de novo (external communication). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Gorlin syndrome Uncertain:1

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 853 of the PTCH1 protein (p.Gln853Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of nevoid basal cell carcinoma syndrome (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 428818). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.69
Sift	Benign	0.26	T
Sift4G	Benign	0.12	T
Polyphen		0.83	P
Vest4		0.81
MutPred		0.51		Loss of helix (P = 0.0196)
MVP		0.89
MPC		1.3
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.82
gMVP		0.93
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0071
dbscSNV1_RF	Benign	0.092
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587778628; hg19: chr9-98229400;