NM_005732.3:c.2301dupC

RAD50 · NP_005723.2:p.(Ile768HisfsTer14) · NM_005732.3

GRCh37: chr5:131939084 A>AC · GRCh38: chr5:132603392 A>AC

Gene: RAD50 Transcript: NM_005732.3

Final call

VUS

PVS1 strong PM2 supporting

Variant details

Gene

RAD50

Transcript

NM_005732.3

Protein

NP_005723.2:p.(Ile768HisfsTer14)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_005732.3:c.2301dup (p.Ile768HisfsTer14) is a frameshift duplication in exon 14 of RAD50, predicted to undergo nonsense-mediated decay. RAD50 loss of function is an established disease mechanism for RAD50 deficiency syndrome.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare pathogenic variant.

No variant-specific functional data, clinical case reports, de novo observations, or segregation data were identified in the reviewed literature. Four RAD50 gene-level publications were reviewed but none reported this specific variant.

Under generic ACMG/AMP 2015 combination rules (PMID:25741868), one strong criterion (PVS1) plus one supporting criterion (PM2) yields a classification of Likely Pathogenic.

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	Met	Frameshift variant NM_005732.3:c.2301dup (p.Ile768HisfsTer14) in exon 14 of 25, predicted to undergo nonsense-mediated decay. RAD50 loss of function is an established disease mechanism for RAD50 deficiency syndrome (PMID:32212377). Under ClinGen SVI PVS1 recommendations (PMC6185798), this null variant in a gene where LOF is a known mechanism meets PVS1 at strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment gnomad_v2 gnomad_v4
PS1	N/A	PS1 requires a different nucleotide change at the same position producing the same amino acid change (same-residue missense comparator rule). This variant is a frameshift duplication, not a missense substitution.
PS2	Not assessed	No de novo observation of this variant has been identified in any reviewed publication or database. No patient-specific clinical data are available.
PS3	Not assessed	No variant-specific functional studies for NM_005732.3:c.2301dupC were identified in the reviewed literature. Four RAD50 gene-level functional publications were reviewed (PMID:12208847, 14684699, 16288216, 21892167) but none evaluated this specific variant.
PS4	Not assessed	No case-control or cohort studies specifically reporting NM_005732.3:c.2301dupC were identified. The variant is absent from ClinVar and COSMIC, and no publication reports it in affected individuals.
PS5	N/A	PS5 requires a different pathogenic missense change at the same amino acid residue. This variant is a frameshift duplication, not a missense substitution.
PM1	Not met	The variant is not located in a statistically significant mutational hotspot (cancerhotspots.org), and no domain-level constraint data support localization in a critical functional domain without benign variation for RAD50 frameshift variants at codon 768.
PM2	Met	NM_005732.3:c.2301dupC is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (HostSeq genomes), meeting the PM2 threshold for absence from population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per adjudication instructions — not assessed in this pass.
PM4	N/A	PM4 applies to in-frame deletions/insertions in nonrepeat regions or stop-loss variants. NM_005732.3:c.2301dupC is a frameshift duplication; null variant effect is captured under PVS1. PM4 is not applicable to frameshift variants per ACMG/AMP 2015 guidance.
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue (same-residue missense comparator). This variant is a frameshift, and no same-residue comparators were identified (pm5_candidates returned not_applicable).
PM6	Not assessed	No de novo report for NM_005732.3:c.2301dupC was identified in any reviewed publication or database. De novo evidence is required to apply PM6.
PP1	Not assessed	No family segregation data are available for NM_005732.3:c.2301dupC. Cosegregation analysis requires genotyping of multiple affected and unaffected family members.
PP2	N/A	PP2 applies specifically to missense variants in genes where missense is a common disease mechanism and benign missense variation is rare. This variant is a frameshift duplication, not a missense variant.
PP3	Not met	REVEL and BayesDel scores are not applicable (variant is not a single nucleotide substitution). SpliceAI predicts no splice impact (max delta score = 0.00). HCI prior score is unavailable for RAD50. No multiple lines of in silico evidence support a deleterious effect.	spliceai
PP4	Not assessed	No patient phenotype or family history information is available for the individual carrying this variant. PP4 requires a phenotype highly specific for a disease with a single genetic etiology.
PP5	Not met	The variant is absent from ClinVar. No reputable source has independently reported this variant as pathogenic. OncoKB classifies it as Likely Oncogenic in a somatic context, which does not constitute a reputable germline source report.	clinvar oncokb
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0 in all populations, well below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases. Allele frequency of 0 is below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No evidence that this variant has been observed in a healthy adult individual with full penetrance expected at an early age, nor observed in trans with a known pathogenic variant for a dominant disorder. Such data are absent from the literature and databases.
BS3	Not assessed	No variant-specific functional studies demonstrating no damaging effect for NM_005732.3:c.2301dupC were identified in the reviewed literature.
BS4	Not assessed	No family cosegregation data are available to demonstrate lack of segregation with disease for NM_005732.3:c.2301dupC.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_005732.3:c.2301dupC is itself a truncating (frameshift) variant, not a missense variant.
BP2	Not met	No evidence that NM_005732.3:c.2301dupC has been observed in trans with a known pathogenic variant in a fully penetrant dominant disorder, or in cis with a known pathogenic variant in any inheritance pattern.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_005732.3:c.2301dupC is a frameshift duplication, not an in-frame variant.
BP4	N/A	BP4 applies to variants for which multiple lines of computational evidence suggest no impact on the gene or gene product. The mechanism of NM_005732.3:c.2301dupC is protein truncation via frameshift, not a missense or splice alteration. SpliceAI shows no splice impact (delta=0.00) but this is not the primary mechanism, and REVEL/BayesDel are not applicable to duplication variants. BP4 is not appropriate for a null variant already evaluated under PVS1.
BP5	Not met	No evidence that NM_005732.3:c.2301dupC has been observed in a case with an alternate molecular basis for disease. No patient-level data are available.
BP6	Not met	No reputable source has independently reported NM_005732.3:c.2301dupC as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact and non-conserved nucleotides. NM_005732.3:c.2301dupC is a frameshift duplication, not a synonymous variant.

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