NM_032444.3:c.1732G>C

SLX4 · NP_115820.2:p.(Glu578Gln) · NM_032444.3

GRCh37: chr16:3646346 C>G · GRCh38: chr16:3596345 C>G

Gene: SLX4 Transcript: NM_032444.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

SLX4

Transcript

NM_032444.3

Protein

NP_115820.2:p.(Glu578Gln)

gnomAD AF

6.261246764500735e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_032444.3:c.1732G>C (p.Glu578Gln) is a missense variant in SLX4, a Fanconi anemia pathway gene (FANCP) with an established loss-of-function disease mechanism.

This variant is extremely rare in population databases, observed in 1/217,630 alleles in gnomAD v2.1 (AF = 0.00046%) and 1/1,597,126 alleles in gnomAD v4.1 (AF = 0.00006%), with no homozygotes, satisfying PM2 at supporting strength.

Multiple in silico predictors indicate a benign effect: REVEL score 0.013, BayesDel score -0.679, and SpliceAI max delta 0.03, satisfying BP4 at supporting benign strength.

ClinVar reports this variant as Uncertain significance (VCV001337411) based on a single clinical laboratory submission; no expert panel review or functional evidence is available.

No variant-specific functional studies, segregation data, de novo reports, or case-control analyses were identified. The sole cited publication (PMID:25741868) is the ACMG/AMP guideline paper and does not mention this variant.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced at Uncertain significance under generic ACMG/AMP 2015 combination rules.

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	Not met	NM_032444.3:c.1732G>C is a missense variant (p.Glu578Gln) and does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable to missense variants under the generic ACMG/AMP framework.	pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No evidence that the same amino acid change (p.Glu578Gln) has been established as pathogenic in a previously classified variant.
PS2	Not met	No de novo occurrence data with confirmed paternity and maternity available for this variant.
PS3	Not met	No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. The sole publication (PMID:25741868) is the ACMG/AMP guideline paper and does not mention this variant.	oncokb
PS4	Not met	No case-control or cohort data comparing variant prevalence in affected versus unaffected individuals. ClinVar reports a single submitter classification of Uncertain significance with no phenotype-specific case series.	clinvar
PS5	Not met	No ClinVar-based PM5/PS5 same-codon pathogenic comparator variants were identified for codon 578.	pm5_candidates
PM1	Not met	This variant does not lie in a statistically significant hotspot (cancerhotspots.org) and no curated functional domain evidence specific to residue 578 was identified in the case materials.
PM2	Met	This variant is extremely rare in population databases: gnomAD v2.1 AF = 4.59e-6 (1/217,630 alleles), v4.1 AF = 6.26e-7 (1/1,597,126 alleles), well below the 0.1% threshold for PM2. Absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same codon (Glu578) with a different amino acid change was identified in ClinVar. Automated PM5 candidate harvesting returned no candidates.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence data (without or with confirmed paternity) available for this variant.
PP1	Not met	No co-segregation data in affected families is available for this variant.
PP2	Not met	No gene-level missense constraint data (e.g., Z-score, gnomAD missense OE ratio) was available in the case materials to assess whether SLX4 has a low rate of benign missense variation.
PP3	Not met	Multiple in silico predictors suggest a benign effect: REVEL score = 0.013 (strongly benign), BayesDel score = -0.679 (benign). These do not support a deleterious effect; rather, they support BP4.	revel bayesdel
PP4	Not met	No patient phenotype or family history data specific to this variant is available. The ClinVar submission lists condition as 'not specified.'	clinvar
PP5	Not met	ClinVar reports this variant as Uncertain significance (1 submitter, criteria provided, single submitter). The review status is not expert panel (0★–1★ equivalent), and the classification is not pathogenic. PP5 requires a pathogenic assertion from a reputable source; a VUS does not qualify.	clinvar
BA1	Not met	gnomAD allele frequency (v2.1: 0.00046%, v4.1: 0.00006%) is far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency (v2.1: 0.00046%, v4.1: 0.00006%) is far below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No data documenting observation of this variant in healthy adults for a disorder with full penetrance expected at an early age.
BS3	Not met	No functional studies (in vitro or in vivo) demonstrating no deleterious effect for this variant. OncoKB reports no variant-specific functional evidence.	oncokb
BS4	Not met	No non-segregation data in affected families is available.
BP1	Not met	Although SLX4 loss-of-function is a supported disease mechanism (Fanconi anemia FANCP subtype), there is insufficient evidence that only truncating variants cause disease in SLX4. Missense variants have been reported in SLX4-associated disease contexts (e.g., endometrial and breast cancer cohorts per PMID:39400928).	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a pathogenic dominant allele or in cis with a pathogenic variant.
BP4	Met	Multiple lines of computational evidence suggest this variant has no deleterious impact: REVEL score = 0.013 (strongly predicts benign), BayesDel score = -0.679 (predicts benign), and SpliceAI max delta = 0.03 (no predicted splice impact).	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease.
BP6	Not met	ClinVar reports this variant as Uncertain significance, not benign. BP6 requires a reputable source to report the variant as benign; a VUS classification does not satisfy this criterion.	clinvar
BP7	N/A	NM_032444.3:c.1732G>C is a missense variant (p.Glu578Gln), not a synonymous or intronic variant. BP7 only applies to synonymous variants with no predicted splice impact.
BP3	N/A	This is a substitution variant, not an in-frame deletion/insertion. BP3 applies to in-frame indels in repeat regions.
PM3	N/A	No second pathogenic variant in trans identified. PM3 requires biallelic observation for recessive disorders.
PM4	N/A	This is a substitution variant, not a protein-length-altering change (non-frameshift indel, stop-loss, initiation codon). PM4 is not applicable.

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.