NM_000465.4:c.562C>T

BARD1 · NP_000456.2:p.(Pro188Ser) · NM_000465.4

GRCh37: chr2:215646036 G>A · GRCh38: chr2:214781312 G>A

Gene: BARD1 Transcript: NM_000465.4

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Pro188Ser)

gnomAD AF

1.2407440493915391e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

BARD1 c.562C>T (p.Pro188Ser) is a missense variant in exon 4 of the BARD1 gene, a moderate-penetrance hereditary breast cancer susceptibility gene where loss of function is the established disease mechanism.

The variant is extremely rare in population databases, with an allele frequency of 0.00040% in gnomAD v2.1 (1/249,196 alleles) and 0.00012% in gnomAD v4.1 (2/1,611,936 alleles), meeting PM2 at moderate strength.

Multiple computational predictors consistently suggest a benign effect: REVEL score 0.05 (benign-tending), BayesDel score -0.484 (strongly benign-tending), and SpliceAI max delta 0.01 (no predicted splice impact), meeting BP4 at supporting benign strength.

Pro188 is located outside the known critical functional domains of BARD1 (RING finger: aa 46-90; ANK repeats: aa 427-555; BRCT domains: aa 615-777) and is not a statistically significant hotspot residue; PM1 is not met.

The variant is classified as Uncertain significance in ClinVar (2 clinical laboratories) with one additional Likely benign submission (Ambry Genetics), all at 1-star review status. No expert panel classification exists; PP5 and BP6 are not met.

Two breast cancer cohort studies cited in ClinVar (PMID:32866190 and PMID:33646313) were reviewed in full text. BARD1 was mentioned at the gene level in both, but the specific variant c.562C>T (p.Pro188Ser) was not reported in either study. No variant-specific functional, segregation, or case-control data were identified.

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	N/A	This is a missense variant (c.562C>T, p.Pro188Ser), not a null variant (nonsense, frameshift, or canonical splice). The PVS1 variant assessment confirms variant_bucket='other' and does not qualify for the generic PVS1 null-variant framework.	pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No established pathogenic variant at codon 188 with the same amino acid change (Pro188Ser) was identified. No same-residue pathogenic comparators were found in ClinVar or the literature.	pm5_candidates
PS2	Not met	No de novo observation was reported for this variant in any reviewed publication. No parental testing data are available.
PS3	Not met	No variant-specific functional studies have been reported. The ClinVar submission (SCV000908589, Color Health) explicitly states 'to our knowledge, functional studies have not been reported for this variant.' No publication identified experimental functional data for Pro188Ser or a systematically characterized range that includes codon 188.	clinvar
PS4	Not met	No case-control or cohort enrichment data are available for this variant. The variant was not specifically reported in any of the ClinVar-cited cohort studies (PMID:32866190, PMID:33646313) despite both being breast cancer gene panel screening studies. Prevalence in affected individuals cannot be assessed.
PS5	Not met	No in vitro or in vivo functional studies demonstrate a damaging effect for this variant. The only functional evidence signals are computational (REVEL, BayesDel), which fall under PP3/BP4, not PS5.
PM1	Not met	Codon 188 (Pro188) lies outside the known critical functional domains of BARD1 (RING finger: aa 46-90; ANK repeats: aa 427-555; BRCT domains: aa 615-777). Cancer Hotspots analysis confirms this residue is not a statistically significant mutational hotspot. No domain-level PM1 evidence applies.
PM2	Met	This variant is extremely rare in population databases, with an overall allele frequency of 0.00040% (1/249,196 alleles) in gnomAD v2.1 and 0.00012% (2/1,611,936 alleles) in gnomAD v4.1, well below the PM2 threshold of 0.1%. It is absent from gnomAD-Canada. No homozygotes are observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variant at codon 188 with a different amino acid change was identified in ClinVar. The PM5 candidate search returned zero same-residue comparator variants.	pm5_candidates
PM6	Not met	No de novo observation with confirmed maternity and paternity has been reported for this variant.
PP1	Not met	No co-segregation data are available for this variant. No family studies were identified in the literature.
PP2	Not met	BARD1 is not established as a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. While loss of function is the primary disease mechanism, pathogenic missense variants are documented in BARD1 (primarily in the RING and BRCT domains). Without a gene-specific Z-score or missense constraint metric in the case materials, PP2 cannot be applied.
PP3	Not met	Multiple computational predictors consistently suggest a benign effect. REVEL score is 0.05 (well below the typical pathogenic threshold of >0.5), BayesDel score is -0.484 (negative, indicating benign), and SpliceAI max delta is 0.01 (no predicted splice impact). These results do not support a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data specific to this variant are available. The ClinVar-cited publications are cohort-level gene panel screening studies that do not report individual variant-level phenotypes.
PP5	Not met	ClinVar classification for this variant is Uncertain significance (2 clinical laboratories) and Likely benign (1 clinical laboratory), with review status of 'criteria provided, single submitter' (1-star). No expert panel has classified this variant as pathogenic. No reputable source reports this variant as pathogenic at a level meeting PP5 criteria.	clinvar
BA1	Not met	The maximum observed allele frequency in any population is 0.00616% (African/African American, gnomAD v2.1), which is well below the BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum observed allele frequency is 0.00616% (AFR, gnomAD v2.1), well below the non-VCEP BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No observation of this variant in a healthy adult individual has been documented for a fully penetrant disorder. The gnomAD observations are at extremely low frequency and without clinical annotation to establish healthy status.
BS3	Not met	No in vitro or in vivo functional studies demonstrate a benign effect for this variant. The only evidence is computational prediction, which falls under BP4.
BS4	Not met	No segregation data are available for this variant to demonstrate lack of co-segregation with disease.
BP1	Not met	While BARD1 disease is primarily driven by loss-of-function truncating variants, pathogenic missense variants are well-documented in BARD1 (especially in the RING and BRCT domains). The gene does not meet the BP1 requirement of having truncating variants as the sole or overwhelmingly predominant disease mechanism. Pro188 lies outside the known functional domains, but BP1 requires gene-level evidence that missense variants are not a common disease mechanism.
BP2	Not met	No observation of this variant in trans with a known pathogenic variant has been reported.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a substitution variant.
BP4	Met	Multiple lines of computational evidence consistently suggest a benign effect. REVEL score is 0.05 (well below pathogenic threshold), BayesDel score is -0.484 (strongly benign-tending), and SpliceAI predicts no splicing impact (max delta = 0.01). No in silico predictor suggests a deleterious effect.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6	Not met	ClinVar reports this variant as Uncertain significance (2 clinical laboratories) and Likely benign (1 clinical laboratory, Ambry Genetics), with a review status of 'criteria provided, single submitter' (1-star). The overall ClinVar classification is VUS. Per PP5/BP6 rules, a 3-star expert panel classification is required for BP6 at supporting benign strength. A 1-star single-submitter Likely benign call does not meet the threshold.	clinvar
BP7	N/A	This is a missense variant (c.562C>T, p.Pro188Ser), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.

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.