About AR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
AR c.2653T>C, p.(Ser885Pro)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 1
Pathogenic criteria applied · 2
PM1Supporting
PM1 · supporting
p.Ser885Pro is located in the androgen receptor ligand-binding domain (LBD, residues ~671-919), a well-established critical functional domain where missense variants are a known cause of androgen insensitivity syndrome. The variant is absent from gnomAD population databases. However, position 885 is not a statistically significant mutational hotspot per cancerhotspots.org, and the residue has not been individually characterized as critical in functional studies. Domain-level PM1 applies at supporting strength.
PM2Moderate
PM2 · moderate
NM_000044.4:c.2653T>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold for a variant absent from large population databases (allele frequency < 0.1%).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no significant impact on the gene product. SpliceAI predicts no splicing alteration (max delta score = 0.00 across all categories). BayesDel score of 0.335 falls in the intermediate range and does not support a damaging prediction. REVEL is unavailable for this variant. The absence of any computational predictor suggesting a deleterious effect supports BP4 at supporting strength.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 supporting, PM2 moderate, BP4 supporting; combination = 1 moderate + 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AR (androgen receptor), a transcription factor, is most frequently altered in advanced or castration-resistant prostate cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 3 met · 19 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000044.4:c.2653T>C (p.Ser885Pro) is a missense variant in exon 8 of AR, encoding the androgen receptor. This variant is absent from gnomAD population databases (v2.1, v4.1, Canada v1.0), meeting PM2 at moderate strength.
The variant is located within the AR ligand-binding domain (residues ~671-919), a well-established critical functional domain where missense variants are a known cause of androgen insensitivity syndrome, meeting PM1 at supporting strength.
Multiple computational predictors suggest no significant impact: SpliceAI delta score is 0.00 and BayesDel score is 0.335 (intermediate, not damaging), meeting BP4 at supporting strength.
The variant is classified as Uncertain significance in ClinVar (VariationID 1410073) by a single clinical laboratory (Labcorp Genetics/Invitae) with review status 'criteria provided, single submitter'. No expert panel classification is available.
No functional studies, case-control data, segregation data, de novo reports, or variant-specific publications were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence.
Applying the generic ACMG/AMP 2015 classification rules (Richards et al. 2015, PMID:25741868): PM2 (moderate) + PM1 (supporting) + BP4 (supporting benign) yields conflicting evidence insufficient to classify as Likely Pathogenic or Likely Benign. The overall classification is Variant of Uncertain Significance (VUS).
No criteria match.
Met · 3
PM1 Supportingp.Ser885Pro is located in the androgen receptor ligand-binding domain (LBD, residues ~671-919), a well-established critical functional domain where missense variants are a known cause of androgen insensitivity syndrome. The variant is absent from gnomAD population databases. However, position 885 is not a statistically significant mutational hotspot per cancerhotspots.org, and the residue has not been individually characterized as critical in functional studies. Domain-level PM1 applies at supporting strength. Details ▾Hide ▴
Evidence considered
- Located in AR ligand-binding domain (residues ~671-919)
- a critical functional domain
- Absent from gnomAD v2.1 and v4.1 — no benign variation at this position
- Not a statistically significant hotspot at residue level (cancerhotspots.org)
Still missing
- No functional characterization specific to residue 885
Sources
PM2 ModerateNM_000044.4:c.2653T>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PM2 threshold for a variant absent from large population databases (allele frequency < 0.1%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. SpliceAI predicts no splicing alteration (max delta score = 0.00 across all categories). BayesDel score of 0.335 falls in the intermediate range and does not support a damaging prediction. REVEL is unavailable for this variant. The absence of any computational predictor suggesting a deleterious effect supports BP4 at supporting strength. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice alteration
- BayesDel = 0.335 — intermediate
- not in damaging range
- REVEL unavailable
Still missing
- REVEL score unavailable for chrX
Sources
spliceai ↗bayesdel
Not met · 19 · evaluated, threshold not reached
PS2 No de novo observation has been reported for NM_000044.4:c.2653T>C. No publications identified in the literature triage describe a de novo occurrence of this variant with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar submissions or literature
Still missing
- No trio sequencing data or de novo reports available for this variant
PS3 No variant-specific functional studies exist for p.Ser885P. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. No publications with experimental functional characterization of this variant or a systematically characterized range including S885 were identified. BayesDel score of 0.335 is intermediate and does not constitute well-established functional evidence for PS3. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect — no variant-specific reviewed functional evidence
- BayesDel score 0.335 — intermediate
- not independently sufficient for PS3
- No publications with functional characterization of p.Ser885P identified
Still missing
- No experimental functional data for this variant
- REVEL score unavailable for chrX
Sources
oncokb ↗bayesdel
PS4 No case-control data or statistical enrichment in affected individuals versus controls is available. The literature triage identified two GeneReviews entries (PMIDs 20301508, 20301602) but neither contains variant-specific case counts for NM_000044.4:c.2653T>C. Details ▾Hide ▴
Evidence considered
- No case counts or prevalence data for this variant in affected individuals
- GeneReviews entries (PMIDs 20301508
- 20301602) are general gene-level reviews without variant-specific observations
Still missing
- No case-control or cohort studies reporting this variant
PM6 No de novo observation with confirmed maternity and paternity has been reported for this variant. PM6 requires a specific de novo report for this exact variant. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar or literature
Still missing
- No de novo testing data available
PP1 No segregation data is available for this variant. No family studies demonstrating co-segregation of c.2653T>C with disease have been identified. Details ▾Hide ▴
Evidence considered
- No segregation data in ClinVar or literature
Still missing
- No family segregation studies
PP2 PP2 requires demonstration that the gene has a low rate of benign missense variation and that missense variants are a common mechanism of disease. The HCI prior lookup for AR returned 'gene_not_supported', precluding automated assessment. While missense variants in AR are a known cause of androgen insensitivity syndrome, the quantitative missense constraint metric is unavailable. Details ▾Hide ▴
Evidence considered
- HCI prior not available for AR (gene_not_supported)
- Missense variants are a known mechanism in AR
- but quantitative constraint data is absent
Still missing
- No HCI prior or missense constraint metric available for AR
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel score is 0.335 (intermediate range, not clearly damaging). REVEL score is unavailable. These do not meet the threshold for PP3, which requires multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice impact
- BayesDel = 0.335 — intermediate
- not clearly damaging
- REVEL unavailable
Still missing
- REVEL score unavailable for chrX
Sources
spliceai ↗bayesdel
PP4 No proband phenotype or family history information is available for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No proband phenotype data available
Still missing
- Proband phenotype and family history not provided
PP5 The ClinVar entry for this variant (VariationID 1410073) is classified as Uncertain significance with review status 'criteria provided, single submitter' (1-star). PP5 requires a reputable source to classify the variant as pathogenic; a VUS classification does not meet this threshold. Under the global PP5/BP6 rule, only ClinVar 3-star expert panel submissions trigger PP5 at supporting strength. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (1 submitter
- 1-star)
- No expert panel pathogenic classification
Sources
BA1 The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada v1.0). BA1 requires an allele frequency > 1% in any population, which is not satisfied. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD — frequency is 0%
- not > 1%
Sources
BS1 The variant is absent from gnomAD population databases. BS1 under the non-VCEP threshold requires allele frequency > 0.3% in any population, which is not satisfied when the variant is completely absent. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases — frequency 0% does not exceed 0.3% threshold
Sources
BS2 No observation of this variant in a healthy adult individual has been reported for a disorder expected to have full penetrance at an early age. The variant is absent from gnomAD and no case reports describe it in unaffected individuals. Details ▾Hide ▴
Evidence considered
- No observation in healthy adults reported
Still missing
- No data on variant presence in healthy adults
BS3 No well-established functional studies demonstrating no damaging effect exist for this variant. OncoKB reports Unknown Oncogenic Effect with no functional data. No publications with experimental benign functional evidence for p.Ser885P were identified. Details ▾Hide ▴
Evidence considered
- No functional studies showing benign effect for p.Ser885P
Still missing
- No experimental functional data of any kind for this variant
Sources
BS4 No segregation data is available to evaluate lack of segregation in affected family members. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No family studies for this variant
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease. AR-related disorders, particularly androgen insensitivity syndrome, are known to be caused by both missense and truncating variants. Missense variants in the AR ligand-binding domain are a well-established disease mechanism, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- Missense variants in AR LBD are a known cause of androgen insensitivity syndrome
- AR disease is not caused primarily by truncating variants
BP2 No observation of this variant in trans with a pathogenic variant has been reported. AR is X-linked, so trans configurations would be relevant primarily in females. Details ▾Hide ▴
Evidence considered
- No observation in trans with a pathogenic variant
Still missing
- No trans-phase data available
BP5 No observation of this variant in a case with an alternate molecular basis for disease has been reported. No proband phenotype or genetic workup data is available for this case. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available
Still missing
- No proband genetic workup data
BP6 The ClinVar entry for this variant (VariationID 1410073) is classified as Uncertain significance, not Benign/Likely Benign. BP6 requires a reputable source to classify the variant as benign. Under the global PP5/BP6 rule, only ClinVar 3-star expert panel benign classifications trigger BP6 at supporting benign strength. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- not Benign
- Single submitter (1-star)
- not expert panel
Sources
PS5 No allele frequency difference between cases and controls has been established for this variant. No case-control literature or genome-wide association data implicating c.2653T>C is available. Details ▾Hide ▴
Evidence considered
- No case-control allele frequency data available
Still missing
- No case-control studies for this variant
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000044.4:c.2653T>C is a missense variant (p.Ser885Pro); it does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant p.Ser885Pro — not a predicted null variant
- PVS1 variant assessment confirms apply_generic_pvs1_framework = false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo previously established pathogenic variant with the same amino acid change at position 885 exists. This variant (p.Ser885Pro) is classified as Uncertain significance in ClinVar (VariationID 1410073) by a single submitter. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Uncertain significance
- not Pathogenic/Likely Pathogenic
- No expert panel or multiple-submitter pathogenic classification for S885P
Sources
PM3 N/ASkipped per directive — AR is X-linked; PM3 (detection in trans with a pathogenic variant for recessive disorders) is trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per directive — NM_000044.4:c.2653T>C is a substitution, not a protein-length-altering variant (in-frame deletion/insertion or stop-loss) that would trigger PM4 assessment. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator variants with a pathogenic classification were identified. The PM5 candidate search found zero candidates at position 885 with expert panel or majority pathogenic/likely pathogenic classification. Details ▾Hide ▴
Evidence considered
- No pathogenic same-residue comparator variants found at S885
Sources
pm5_candidates
BP3 N/ASkipped per directive — NM_000044.4:c.2653T>C is a substitution, not an in-frame deletion/insertion in a non-repeat region that would trigger BP3 assessment. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_000044.4:c.2653T>C is a missense variant (p.Ser885Pro), not a synonymous variant. BP7 applies exclusively to synonymous variants where splicing algorithms predict no impact. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Ser885Pro)
- not synonymous
Identifiers
- Gene
- AR
- Transcript
- NM_000044.4
- Coding (HGVS c.)
- NM_000044.4:c.2653T>C
- Protein (HGVS p.)
- NP_000035.2:p.(Ser885Pro)
- GRCh38
- chrX:67723731 T>C
- GRCh37
- chrX:66943573 T>C
- ClinVar
- 1410073
Gene diagram
Every interpreted variant in AR, mapped onto the exon structure of NM_000044.4. Select a row to find it on the plot.
ARNM_000044.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in AR
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.335
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. SpliceAI predicts no splicing alteration (max delta score = 0.00 across all categories). BayesDel score of 0.335 falls in the intermediate range and does not support a damaging prediction. REVEL is unavailable for this variant. The absence of any computational predictor suggesting a deleterious effect supports BP4 at supporting strength. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice alteration
- BayesDel = 0.335 — intermediate
- not in damaging range
- REVEL unavailable
Still missing
- REVEL score unavailable for chrX
Sources
spliceai ↗bayesdel
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). BayesDel score is 0.335 (intermediate range, not clearly damaging). REVEL score is unavailable. These do not meet the threshold for PP3, which requires multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice impact
- BayesDel = 0.335 — intermediate
- not clearly damaging
- REVEL unavailable
Still missing
- REVEL score unavailable for chrX
Sources
spliceai ↗bayesdel
BP7 N/ANM_000044.4:c.2653T>C is a missense variant (p.Ser885Pro), not a synonymous variant. BP7 applies exclusively to synonymous variants where splicing algorithms predict no impact. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Ser885Pro)
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.335265.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 20301508 ↗Spinal and Bulbar Muscular Atrophy.Adam MP et al. · 1993Spinal and Bulbar Muscular Atrophy (Kennedy disease) GeneReviews entry. Discusses AR CAG repeat expansion as the molecular basis of SBMA. NM_000044.4:c.2653T>C (p.Ser885Pro) was not identified in this publication.Does not name this variant
-
PMID 20301602 ↗Androgen Insensitivity Syndrome.Adam MP et al. · 1993Androgen Insensitivity Syndrome GeneReviews entry. Discusses AR mutations broadly as the cause of AIS, including missense variants in the ligand-binding domain. NM_000044.4:c.2653T>C (p.Ser885Pro) was not identified in this publication.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1410073/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/X-66943573-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chrX-67723731-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/X-67723731-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000044.4%3Ac.2653…
- OncoKB ↗www.oncokb.org/gene/AR/S885P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=AR+c.2653T%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1410073)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.335265.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AR (androgen receptor), a transcription factor, is most frequently altered in advanced or castration-resistant prostate cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.