NM_000465.4:c.2127A>G

BARD1 · NP_000456.2:p.(Pro709=) · NM_000465.4

GRCh37: chr2:215593607 T>C · GRCh38: chr2:214728883 T>C

Gene: BARD1 Transcript: NM_000465.4

Final call

VUS

BP7_Supporting

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Pro709=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BARD1 c.2127A>G (p.Pro709=) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with Likely benign and Benign submissions.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0, which is below the benign frequency thresholds and does not by itself support pathogenicity for a synonymous variant.

In silico analysis predicts no meaningful splice effect, with a SpliceAI maximum delta score of 0.00, and the variant is synonymous at p.Pro709=, supporting BP7 and not supporting PP3.

Final determination: BP7 supporting alone does not meet the ACMG/AMP combination threshold for likely benign or benign classification; therefore the variant remains 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 variant is a synonymous substitution, NM_000465.4:c.2127A>G (p.Pro709=), and does not create a predicted loss-of-function allele; PVS1 is therefore not applicable.	prefetch case_summary
PS1	N/A	This variant does not change the amino acid sequence and is not a missense change matching a known pathogenic amino acid substitution, so PS1 is not applicable.	prefetch case_summary
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified, so PS2 was not assessed.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not assessed.	evidence literature_pass
PS4	Not met	Available evidence does not show that this variant is enriched in affected individuals compared with controls. No case-control data, no quantified excess of affected carriers, and no COSMIC somatic observations were identified, so PS4 is not met.	clinvar cosmic screen_PS4
PM1	Not met	This variant has not been shown to occur in a well-established critical functional domain or mutational hotspot without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at residue P709, so PM1 is not met.	hotspots case_summary
PM2	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, but absence from population databases alone does not establish pathogenicity for a synonymous variant; PM2 is therefore not met.	gnomad_v2 gnomad_v4
PM3	N/A	No recessive disease context or trans observation relevant to PM3 was identified for this variant, so PM3 is not applicable.
PM4	N/A	This variant does not change protein length and is not an in-frame insertion or deletion, so PM4 is not applicable.	prefetch case_summary
PM5	N/A	This variant is not a novel missense change at an amino acid residue with a different established pathogenic missense change, so PM5 is not applicable.	prefetch case_summary
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified, so PM6 was not assessed.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	literature_pass
PP2	N/A	This variant is not a missense change, so PP2 is not applicable.	prefetch case_summary
PP3	Not met	Available in silico evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the REVEL score is 0.123, so PP3 is not met.	spliceai prefetch screen_PP3
PP4	Not assessed	No phenotype or family history information specific enough to support a highly specific BARD1-related presentation was identified, so PP4 was not assessed.
PP5	Not assessed	ClinVar lists this variant as Likely benign and Benign, not pathogenic, and current ACMG/AMP practice does not use database assertions alone to apply PP5; PP5 was therefore not assessed.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0 and is below the benign stand-alone threshold of 1%; BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its observed population frequency is 0 and is below the benign strong threshold of 0.3%; BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a context sufficient to apply BS2, so BS2 was not assessed.
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect for this specific variant were identified, so BS3 was not assessed.	evidence literature_pass
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 was not assessed.
BP1	N/A	This variant is synonymous rather than missense, so BP1 is not applicable.	prefetch case_summary
BP2	Not assessed	No phase information demonstrating this variant in trans with a pathogenic variant for a dominant disorder, or in cis for any disorder, was identified, so BP2 was not assessed.
BP3	N/A	This variant is not an in-frame insertion or deletion in a repetitive region, so BP3 is not applicable.	prefetch case_summary
BP4	N/A	For this synonymous variant, benign computational evidence is more appropriately captured under BP7 rather than BP4, so BP4 was not applied separately.	spliceai prefetch
BP5	Not assessed	No alternate molecular explanation for the phenotype was identified in the available evidence, so BP5 was not assessed.
BP6	Not assessed	Although ClinVar includes Likely benign and Benign submissions for this variant, database assertions alone were not used to apply BP6; BP6 was not assessed.	clinvar
BP7	Met	This variant is a synonymous change, NM_000465.4:c.2127A>G (p.Pro709=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Available evidence is consistent with no effect on splicing or protein sequence, so BP7 is met at supporting strength.	prefetch case_summary spliceai screen_BP7

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