Classification rationale

PM2 VUS

AR c.515C>T

NM_000044.4:c.515C>T (p.Pro172Leu) is a missense variant in the androgen receptor (AR) gene, located on the X chromosome. This variant is absent from large population databases including gnomAD v2.1 (0/154,879 alleles) and gnomAD v4.1, meeting PM2 at supporting strength.¹ No variant-specific functional, segregation, case-control, or de novo data were identified. ClinVar classifies this variant as Uncertain Significance (Variation ID 4538436) with a single submitter and no assertion criteria provided.² With only one supporting-level pathogenic criterion (PM2_supporting) and no benign criteria met, the overall classification is Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.³

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 clinvar ↗

3 generic_acmg_combination_rules

Gene diagram · NM_000044.4 · variants mapped to exon structure

AR NM_000044.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 21 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_000044.4:c.515C>T is absent from large population databases: gnomAD v2.1 (0/154,879 alleles, AF=0.00%) and gnomAD v4.1 (absent). This meets the PM2 threshold for rare variants (allele frequency <0.1% in all populations).

gnomAD v2.1: 0/154879 alleles (0.00%)gnomAD v4.1: absent

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied

Pathogenic

PS1 No data available on a different nucleotide change at codon 172 producing the same amino acid change (Pro172Leu) that has been classified as pathogenic.

PS2 No de novo reports for NM_000044.4:c.515C>T with confirmed maternity and paternity were identified.

PS3 No variant-specific functional evidence was identified for NM_000044.4:c.515C>T (p.Pro172Leu).

PS4 No case-control data or systematic case series demonstrating increased prevalence of NM_000044.4:c.515C>T in affected individuals compared to controls.

PM1 Residue Pro172 is located in the N-terminal transactivation domain (NTD) of AR (residues 1–555), which is a functionally important region.

PM6 No de novo observation (assumed or confirmed) exists for this variant.

PP1 No co-segregation data are available for NM_000044.4:c.515C>T.

PP2 AR is an X-linked gene where missense variants are a known mechanism of disease (Androgen Insensitivity Syndrome).

PP3 In silico evidence is insufficient to meet PP3: the sole available predictor (BayesDel score 0.277) is borderline and not corroborated by additional computational evidence.

PP4 No patient phenotype or family history data were provided in the case materials.

PP5 ClinVar classifies NM_000044.4:c.515C>T as 'Uncertain significance' (Variation ID 4538436) with review status 'no assertion criteria provided' and a single submitter using provider interpretation.

Benign

BA1 NM_000044.4:c.515C>T is absent from gnomAD v2.1 (0/154,879 alleles) and gnomAD v4.1.

BS1 NM_000044.4:c.515C>T is absent from population databases (gnomAD AF=0.00%), far below the BS1 threshold of >0.3%.

BS2 No observation of NM_000044.4:c.515C>T in a healthy adult hemizygous male has been reported.

BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect of NM_000044.4:c.515C>T (p.Pro172Leu) on AR protein function were identified.

BS4 No segregation data are available to assess lack of segregation with disease in affected family members.

BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease.

BP2 AR is X-linked; Androgen Insensitivity Syndrome affects 46,XY individuals.

BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene product.

BP5 No alternate molecular basis for disease has been identified in a case harboring NM_000044.4:c.515C>T.

BP6 No reputable source classifies NM_000044.4:c.515C>T as benign.

N/A · 6 PVS1 · PM3 · PM4 · PM5 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/154879 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/10641 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / 154,879
0 hom

Not observed in any ancestry group.

+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar but submission details could not be extracted. (ClinVarID = 4538436)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.276959.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

20301602 ↗ Androgen Insensitivity Syndrome. CLINVAR