LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_000264.5:c.324A>G
PTCH1
· NP_000255.2:p.(Ile108Met)
· NM_000264.5
GRCh37: chr9:98268759 T>C
·
GRCh38: chr9:95506477 T>C
Gene:
PTCH1
Transcript:
NM_000264.5
Final call
VUS
PM2 supporting
BS2 supporting
Variant details
Gene
PTCH1
Transcript
NM_000264.5
Protein
NP_000255.2:p.(Ile108Met)
gnomAD AF
0.00016178421333201096 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 (Supporting): gnomAD v4.1 allele frequency 0.01618% is below the 0.1% rarity threshold.
2
BS2 (Supporting): one homozygous carrier in gnomAD v4.1 is inconsistent with a highly penetrant autosomal-dominant PTCH1 disorder.
3
VUS: PM2 and BS2 conflict at supporting strength, meeting no pathogenic or benign combination threshold under the generic ACMG/AMP 2015 rules.
Final determination:
Under the generic ACMG/AMP 2015 fallback, one pathogenic supporting criterion (PM2) and one benign supporting criterion (BS2) are conflicting evidence that does not meet any definitive classification combination, resulting in VUS.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
| Criterion | Status | Rationale | Evidence used |
|---|---|---|---|
| PVS1 | N/A | Not applicable: c.324A>G is a missense change, not a null variant class (nonsense, frameshift, or canonical splice-site). |
pvs1_generic_framework
generic_acmg_combination_rules
|
| PS1 | Not met | Not met: the same protein change was reported in one proband but never established as pathogenic (inherited from an unaffected mother). |
PMID:32074614
|
| PS2 | Not assessed | Not assessed: no de novo occurrence is documented; the variant was inherited from the proband's unaffected mother. |
PMID:32074614
|
| PS3 | Not assessed | Not assessed: no validated variant-specific functional assay demonstrating a damaging effect was available. |
oncokb
PMID:32074614
|
| PS4 | Not assessed | Not assessed: the variant was seen in one proband only, with no case-control or enrichment data. |
PMID:32074614
|
| PM1 | Not met | Not met: p.Ile108Met is not in a statistically significant cancer hotspot. |
oncokb
|
| PM2 | Met | Met (supporting): gnomAD v4.1 allele frequency 0.01618% is below the 0.1% PM2 cutoff. |
gnomad_v4
gnomad_v2
gnomad_canada
PMID:32074614
|
| PM3 | N/A | Not applicable: PTCH1-related Gorlin syndrome is autosomal dominant, so recessive trans-allele evidence does not apply. |
PMID:32074614
|
| PM4 | N/A | Not applicable: this missense change does not alter protein length, so PM4's in-frame indel/stop-loss premise does not apply. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| PM5 | Not met | Not met: no confirmed pathogenic missense change at residue 108 is available as a comparator. |
PMID:32074614
|
| PM6 | Not assessed | Not assessed: no de novo occurrence with incomplete parental testing is reported. |
PMID:32074614
|
| PP1 | Not assessed | Not assessed: no family segregation data are reported for this variant. |
PMID:32074614
|
| PP2 | Not assessed | Not assessed: no quantitative evidence shows PTCH1 has a low rate of benign missense variation. |
|
| PP3 | Not met | Not met: REVEL score 0.603 falls in the gray zone between the >0.750 PP3 and <0.250 BP4 thresholds. |
revel
spliceai
generic_acmg_combination_rules
PMID:32074614
|
| PP4 | Not assessed | Not assessed: the reported proband had isolated Kallmann syndrome without Gorlin-Goltz features. |
PMID:32074614
|
| PP5 | Not assessed | Not assessed: no ClinVar expert-panel pathogenic classification exists for this variant. |
clinvar
|
| BA1 | Not met | Not met: highest population allele frequency 0.04484% is far below the 1% BA1 threshold. |
gnomad_v4
gnomad_v2
gnomad_canada
|
| BS1 | Not met | Not met: highest observed allele frequency 0.04484% is below the 0.3% BS1 threshold. |
gnomad_v4
gnomad_v2
gnomad_canada
|
| BS2 | Met | Met (supporting): one homozygous carrier in gnomAD v4.1 is inconsistent with a highly penetrant dominant PTCH1 disorder. |
gnomad_v4
PMID:32074614
|
| BS3 | Not assessed | Not assessed: no validated functional assay demonstrating a benign effect was available. |
oncokb
PMID:32074614
|
| BS4 | Not assessed | Not assessed: inheritance from an unaffected mother does not formally establish lack of segregation with a PTCH1-related phenotype. |
PMID:32074614
|
| BP1 | Not assessed | Not assessed: no framework establishes that disease-causing PTCH1 variants are primarily truncating. |
PMID:32074614
|
| BP2 | Not assessed | Not assessed: no co-occurring second PTCH1 variant is reported; an unaffected parent alone does not qualify. |
PMID:32074614
|
| BP3 | N/A | Not applicable: BP3 concerns in-frame indels in repetitive regions; this missense change does not qualify. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| BP4 | Not met | Not met: REVEL score 0.603 is above the <0.250 BP4 threshold and in the calibrated gray zone. |
revel
spliceai
generic_acmg_combination_rules
|
| BP5 | Not assessed | Not assessed: no independent molecular diagnosis fully explaining the phenotype is identified. |
|
| BP6 | Not assessed | Not assessed: no ClinVar expert-panel benign classification exists for this variant. |
clinvar
|
| BP7 | N/A | Not applicable: BP7 applies only to synonymous variants; this missense change is outside its scope. |
generic_acmg_combination_rules
|
Disclaimer:
The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.