Starting

Initialising…

BARD1

Final classification

VUS

BARD1 c.62G>T · p.Arg21Leu

BARD1

Gene

BARD1

Transcript

NM_000465.4

HGVS · transcript:coding

NM_000465.4:c.62G>T

Consequence

N/A

GRCh38

chr2:214809508 C>A

GRCh37

chr2:215674232 C>A

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.

Classification rationale

PM2 BP4 VUS

BARD1 c.62G>T

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.¹ 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.² 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.

PM2 + BP4 → VUS

1 hotspots ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

Gene diagram · NM_000465.4 · variants mapped to exon structure

BARD1 NM_000465.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1601354 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74788 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,601,354
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.16. BayesDel score = -0.392235.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BARD1, a tumor suppressor involved in the DNA damage response, is altered by mutation in breast and ovarian cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53613702, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots