NM_000044.4:c.2653T>C

AR · NP_000035.2:p.(Ser885Pro) · NM_000044.4

GRCh37: chrX:66943573 T>C · GRCh38: chrX:67723731 T>C

Gene: AR Transcript: NM_000044.4

Final call

VUS

PM1 supporting PM2 moderate BP4 supporting

Variant details

Gene

Transcript

NM_000044.4

Protein

NP_000035.2:p.(Ser885Pro)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_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).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No 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.	clinvar
PS2	Not met	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.
PS3	Not met	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.	oncokb bayesdel
PS4	Not met	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.
PS5	Not met	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.
PM1	Met	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.	gnomad_v2 gnomad_v4
PM2	Met	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%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	Not met	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.
PP1	Not met	No segregation data is available for this variant. No family studies demonstrating co-segregation of c.2653T>C with disease have been identified.
PP2	Not met	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.
PP3	Not met	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.	spliceai bayesdel
PP4	Not met	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.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.
BS3	Not met	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.	oncokb
BS4	Not met	No segregation data is available to evaluate lack of segregation in affected family members. No family studies have been reported for this variant.
BP1	Not met	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.
BP2	Not met	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.
BP4	Met	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.	spliceai bayesdel
BP5	Not met	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.
BP6	Not met	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.	clinvar
BP7	N/A	NM_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.
BP3	N/A	Skipped 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.
PM3	N/A	Skipped per directive — AR is X-linked; PM3 (detection in trans with a pathogenic variant for recessive disorders) is trivially not applicable.
PM4	N/A	Skipped 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.

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.