NM_000465.4:c.62G>T

BARD1 · NP_000456.2:p.(Arg21Leu) · NM_000465.4

GRCh37: chr2:215674232 C>A · GRCh38: chr2:214809508 C>A

Gene: BARD1 Transcript: NM_000465.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Arg21Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BARD1 c.62G>T (p.Arg21Leu) variant has not been identified in a statistically significant cancer hotspot and has been reported in ClinVar as a variant of uncertain significance by a single submitter.

This variant is absent from gnomAD v2.1 and has 0/1,601,354 alleles in gnomAD v4.1 (AF 0.0%), which is below the 0.1% threshold used for PM2 and supports rarity in population databases.

Available computational evidence does not support a damaging effect, with a REVEL score of 0.16 and a BayesDel score of -0.392235, supporting benign computational evidence rather than pathogenic computational evidence.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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, p.(Arg21Leu), and it does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Although loss of function is an established disease mechanism for BARD1, available evidence does not support applying PVS1 to this specific variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that another nucleotide change causing the same amino acid substitution, p.(Arg21Leu), has already been established as pathogenic or likely pathogenic.
PS2	Not assessed	No confirmed de novo observation with verified maternity and paternity was identified.
PS3	Not assessed	No well-established functional study showing a damaging effect of this specific variant was identified.	oncokb
PS4	Not assessed	No case-control enrichment or multiple independent affected observations were identified to show that this variant is significantly increased in affected individuals over controls.	clinvar
PM1	Not met	This variant has not been identified in a statistically significant hotspot, and available evidence does not show that codon 21 lies in a well-established critical region without benign variation.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and has 0/1,601,354 alleles in gnomAD v4.1 (AF 0.0%), which is below the 0.1% rarity threshold used for PM2 in this framework. This supports that the variant is rare in population databases.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is used for recessive disorders when pathogenic variants are observed in trans. That evidence model is not applicable to this BARD1 hereditary cancer susceptibility evaluation.
PM4	N/A	This is a missense substitution and does not change protein length or create an in-frame insertion or deletion.
PM5	Not assessed	No evidence was identified showing that a different missense change at the same amino acid residue has already been established as pathogenic or likely pathogenic.
PM6	Not assessed	No assumed de novo observation without confirmed parentage was identified.
PP1	Not assessed	No segregation data were identified to show that this variant tracks with disease in affected family members.
PP2	Not assessed	Available evidence does not establish that pathogenic missense variation is a common disease mechanism in BARD1 or that this gene has a low rate of benign missense variation sufficient for PP2.
PP3	Not met	Available computational evidence does not support a deleterious effect. The observed missense prediction scores are low and do not support applying pathogenic computational evidence.
PP4	Not assessed	No phenotype or family history data were identified showing a highly specific clinical presentation attributable to a single genetic cause for this variant assessment.
PP5	Not met	ClinVar reports this variant as uncertain significance rather than pathogenic or likely pathogenic, so external classification evidence does not support PP5.	clinvar
BA1	Not met	Population frequency does not meet the standalone benign threshold. The variant is absent from gnomAD v2.1 and has 0/1,601,354 alleles in gnomAD v4.1, which is below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not support a benign interpretation. The variant is absent from gnomAD v2.1 and has 0/1,601,354 alleles in gnomAD v4.1, which is below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a manner sufficient to support a benign classification.
BS3	Not assessed	No well-established functional study showing a normal or benign effect for this specific variant was identified.	oncokb
BS4	Not assessed	No segregation data were identified showing lack of segregation with disease.
BP1	Not assessed	Available evidence does not establish that missense variants in BARD1 are generally less likely to be pathogenic than truncating variants to a degree sufficient for BP1.	pvs1_gene_context
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in a way that would support BP2.
BP3	N/A	This is not an in-frame insertion or deletion in a repetitive region.
BP4	Met	Available computational evidence favors a benign effect for this missense change. REVEL is 0.16 and BayesDel is -0.392235, which do not support a damaging protein effect.
BP5	Not assessed	No alternate molecular explanation was identified for the phenotype that would support BP5.
BP6	Not met	ClinVar does not report this variant as benign or likely benign, so external classification evidence does not support BP6.	clinvar
BP7	N/A	BP7 applies to synonymous or certain intronic variants without predicted splice impact. This variant is a missense substitution and BP7 does not apply.

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.