Variant classification summary

NM_002878.4:c.694C>T

RAD51D · NP_002869.3:p.(Arg232Ter) · NM_002878.4

GRCh37: chr17:33430317 G>A · GRCh38: chr17:35103298 G>A

Gene: RAD51D Transcript: NM_002878.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

RAD51D

Transcript

NM_002878.4

Protein

NP_002869.3:p.(Arg232Ter)

gnomAD AF

1.178860426648202e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PVS1 very strong supports a truncating RAD51D loss-of-function allele with predicted nonsense-mediated decay.

2

Likely Pathogenic: PM2 supporting shows a maximum gnomAD allele frequency of 3.21e-05 and zero homozygotes.

Final determination: Under the generic ACMG/AMP fallback, one very strong pathogenic criterion plus one supporting pathogenic criterion leads to Likely Pathogenic.

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	Met at very strong: c.694C>T creates p.Arg232Ter in exon 8 of 10, predicting nonsense-mediated decay and loss of 98 of 329 amino acids.	pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context PMID:21822267 PMID:27083178
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_002878.4:c.694C>T in RAD51D is a nonsense substitution introducing a premature stop codon predicted to produce NP_002869.3:p.(Arg232Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no confirmed de novo observation with parental testing is documented for the proband.	PMID:27083178
PS3	Not assessed	Not assessed: no validated assay tested RAD51D c.694C>T (p.Arg232Ter), while available functional studies evaluated other or unspecified RAD51D loss-of-function variants.	PMID:21822267 PMID:22986143 PMID:27083178 generic_acmg_combination_rules
PS4	Not assessed	Not assessed: the exact variant was observed in 1 of 105 tested patients without a variant-specific control comparison, odds ratio, or significant enrichment statistic.	PMID:27083178
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_002878.4:c.694C>T in RAD51D is a nonsense substitution introducing a premature stop codon predicted to produce NP_002869.3:p.(Arg232Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met at supporting: gnomAD maximum observed allele frequency 3.21e-05 is below the PM2 threshold of <=0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: the reported c.694C>T case has no documented second RAD51D variant or phase information establishing a biallelic affected genotype.	PMID:27083178
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002878.4:c.694C>T in RAD51D is a nonsense substitution introducing a premature stop codon predicted to produce NP_002869.3:p.(Arg232Ter). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_002878.4:c.694C>T in RAD51D is a nonsense substitution introducing a premature stop codon predicted to produce NP_002869.3:p.(Arg232Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: a patient report exists, but no assumed-de novo pedigree or parental-status evidence is documented.	PMID:27083178
PP1	Not assessed	Not assessed: zero informative variant-positive affected relatives or meioses are documented for this exact variant.	PMID:27083178 PMID:21822267 PMID:22986143
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_002878.4:c.694C>T in RAD51D is a nonsense substitution introducing a premature stop codon predicted to produce NP_002869.3:p.(Arg232Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the variant is nonsense, p.(Arg232Ter), and PP3 is restricted to missense or splice-region/intronic computational assessment.
PP4	Not assessed	Not assessed: the available report lacks a complete individual phenotype and family history sufficiently specific for RAD51D-related disease.	PMID:27083178
PP5	Not met	Not met: the exact variant has zero ClinVar expert-panel submissions, despite multiple laboratory Pathogenic or Likely pathogenic assertions.	clinvar
BA1	Not met	Not met: gnomAD maximum observed allele frequency 3.21e-05 is far below the generic BA1 stand-alone threshold of >=0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD maximum observed allele frequency 3.21e-05 is below the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 report zero homozygotes, so no BS2 evidence of healthy homozygous occurrence is present.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no validated assay demonstrated preserved RAD51D function for c.694C>T (p.Arg232Ter), and the exact-variant report supplied no functional result.	PMID:21822267 PMID:22986143 PMID:27083178 generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no phenotype-negative relatives with confirmed variant status are documented for non-segregation analysis.	PMID:27083178
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_002878.4:c.694C>T in RAD51D is a nonsense substitution introducing a premature stop codon predicted to produce NP_002869.3:p.(Arg232Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: c.694C>T is reported without a second pathogenic allele or phase result showing cis or trans configuration.	PMID:27083178
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002878.4:c.694C>T in RAD51D is a nonsense substitution introducing a premature stop codon predicted to produce NP_002869.3:p.(Arg232Ter). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the variant is nonsense, p.(Arg232Ter), and BP4 is restricted to missense or splice-region/intronic computational assessment.
BP5	Not assessed	Not assessed: no confirmed alternative molecular diagnosis or applicable BP5 thresholded evidence was available for this patient.
BP6	Not met	Not met: the exact variant has no ClinVar expert-panel Benign or Likely benign classification and instead has laboratory Pathogenic or Likely pathogenic assertions.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002878.4:c.694C>T in RAD51D is a nonsense substitution introducing a premature stop codon predicted to produce NP_002869.3:p.(Arg232Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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