NM_000465.4:c.1325C>T

BARD1 · NP_000456.2:p.(Pro442Leu) · NM_000465.4

GRCh37: chr2:215634026 G>A · GRCh38: chr2:214769302 G>A

Gene: BARD1 Transcript: NM_000465.4

Final call

Likely Benign

PM2 supporting BP1 supporting benign BP4 supporting benign

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Pro442Leu)

gnomAD AF

2.3559901048415597e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000465.4:c.1325C>T (p.Pro442Leu) is a missense variant in BARD1 present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00119%; v4.1 AF=0.00236%), meeting PM2 at supporting level.

Multiple in silico tools consistently predict a benign effect: REVEL score 0.208, BayesDel score -0.244, and SpliceAI max delta 0.07, meeting BP4 at supporting level.

BARD1 is a tumor suppressor gene where primarily loss-of-function variants cause disease; this missense variant meets BP1 at supporting level.

No functional studies, case-control data, de novo observations, co-segregation data, or pathogenic same-residue comparators exist for this variant. ClinVar classifies it as a Variant of Uncertain Significance (9 clinical laboratories).

Two supporting benign criteria (BP1 and BP4) are met with no moderate or strong criteria on either side. Per generic ACMG/AMP 2015 combination rules, two supporting benign criteria warrant a classification of Likely Benign.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	PVS1 applies only to null variants (nonsense, frameshift, or canonical splice site variants). NM_000465.4:c.1325C>T is a missense variant (p.Pro442Leu) in exon 5 and does not fall into any PVS1 null-variant bucket.	pvs1_variant_assessment
PS1	Not met	No known pathogenic variant at amino acid position 442 (Pro442) with a different substitution has been identified in ClinVar or the reviewed literature. PS1 requires a pathogenic missense change at the same residue.	clinvar pm5_candidates
PS2	Not assessed	No de novo data are available for this variant. PS2 requires a de novo observation with confirmed maternity and paternity.
PS3	Not met	No functional studies have directly tested BARD1 Pro442Leu or a systematically characterized range that includes position 442. ClinVar submissions explicitly note that functional studies have not been reported for this variant. In silico predictions are BP4 territory, not PS3.	clinvar oncokb
PS4	Not met	No case-control studies or sufficient enrichment data in affected individuals are available for this variant. The ClinVar-associated PMIDs are practice guidelines and consensus statements, not observational studies reporting variant prevalence in affected vs. unaffected cohorts.	clinvar
PS5	Not assessed	No de novo observation with confirmed maternity and paternity has been reported for this variant. PS5 (new in Tavtigian et al. 2018) requires a proven de novo occurrence.
PM1	Not met	The variant (p.Pro442Leu) does not lie in a statistically significant mutational hotspot as assessed by cancerhotspots.org. Although position 442 falls within the BARD1 ANK repeat region (aa ~420-555), no domain-specific characterization data were identified in the case materials to support PM1 at domain level, and no ClinVar PM1 signal was raised by any submitter.
PM2	Met	This variant is present at extremely low frequency in population databases. gnomAD v2.1: 3/251,198 alleles (AF=0.00119%); gnomAD v4.1: 38/1,612,910 alleles (AF=0.00236%); absent from gnomAD-Canada. All allele frequencies are well below the 0.1% PM2 threshold. No homozygotes observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic comparator variant was identified. PM5 requires a different pathogenic missense change at the same amino acid position.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant. PM6 requires a de novo event with unconfirmed parentage.
PP1	Not assessed	No co-segregation data are available for this variant. PP1 requires evidence of co-segregation with disease in multiple affected family members.
PP2	Not met	BARD1 is a tumor suppressor gene where loss-of-function (truncating, nonsense, splice) variants are the established disease mechanism. Missense variants are not a common mechanism of disease for BARD1; PP2 does not apply.	pvs1_gene_context
PP3	Not met	Multiple in silico tools predict a benign effect for this variant: REVEL score 0.208 (well below the pathogenic threshold of ~0.5), BayesDel score -0.243647 (negative, benign), and SpliceAI max delta 0.07 (no predicted splice impact). These do not support a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or specific clinical data are available for the individuals carrying this variant. PP4 requires a phenotype highly specific for the gene/disease.
PP5	Not met	This variant is classified as Uncertain Significance (VUS) in ClinVar by 9 clinical laboratories, not Pathogenic or Likely Pathogenic. The ClinVar-associated PMIDs are practice guidelines, review articles, and consensus statements that do not reference this specific variant. None of the candidate PP5 papers mention NM_000465.4:c.1325C>T.	clinvar
BA1	Not met	The allele frequency of this variant in gnomAD v2.1 (0.00119%) and v4.1 (0.00236%) is well below the 1% BA1 threshold. The variant is too rare to apply BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency of this variant (gnomAD v2.1: 0.00119%, v4.1: 0.00236%) is below the 0.3% BS1 threshold. The variant is not sufficiently common in population databases to apply BS1.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence is available that this variant has been observed in healthy adults with full penetrance expected at an early age. The three gnomAD observations do not include phenotype data, and there are no published reports of this variant in healthy controls.
BS3	Not met	No functional studies demonstrating a neutral or benign effect exist for this variant. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. In silico predictions alone (BP4) do not constitute BS3 evidence.
BS4	Not assessed	No co-segregation data demonstrating lack of segregation with disease are available. BS4 requires observation that the variant does not segregate with disease in affected family members.
BP1	Met	BARD1 is a tumor suppressor gene where primarily loss-of-function (truncating, nonsense, splice-disrupting) variants are known to cause disease. NM_000465.4:c.1325C>T is a missense variant (p.Pro442Leu), and missense variants are not the established disease mechanism for BARD1.	pvs1_gene_context
BP2	Not met	No evidence that this variant has been observed in trans with a known pathogenic variant in BARD1. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in a recessive disorder.
BP4	Met	Multiple lines of computational evidence support a benign effect: REVEL score 0.208 (well below the pathogenic threshold of ~0.5), BayesDel score -0.243647 (negative/benign), and SpliceAI max delta score 0.07 (no predicted splice impact). These independent in silico tools consistently suggest this missense change is tolerated.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease has been reported. BP5 requires that the variant be found in a patient with an alternate cause of their disease.
BP6	Not met	ClinVar classifies this variant as Uncertain Significance, not Benign or Likely Benign. No expert panel or reputable source has classified this variant as benign. BP6 requires a reputable source to classify the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_000465.4:c.1325C>T is a missense variant (p.Pro442Leu), not a synonymous variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This is a substitution variant.
PM3	N/A	PM3 applies to recessive disorders with a pathogenic variant observed in trans. BARD1-associated cancer predisposition is inherited in an autosomal dominant manner.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. This is a substitution variant.

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