2-214752510-AC-GT

Variant names:

• chr2-214752510-AC-GT
• NM_000465.4:c.1613_1614delGTinsAC
• BARD1 p.Ser538Asn

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_SupportingB2_Supporting

The NM_000465.4(BARD1):c.1613_1614delGTinsAC (p.Ser538Asn) variant causes a missense change. The gene BARD1 is a tumor suppressor gene (CancerMine: 7 TSG, 5 oncogene citations). The gene BARD1 is a known oncogene (CancerMine: 7 TSG, 5 oncogene citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S538N: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 186171); p.S538R: Uncertain_significance (ClinVar VariationId 3240860, 2 stars); p.S538= (synonymous): Benign/Likely_benign (ClinVar VariationId 629875, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 0 publications found

Genes affected

BARD1 (HGNC:952): (BRCA1 associated RING domain 1) This gene encodes a protein which interacts with the N-terminal region of BRCA1. In addition to its ability to bind BRCA1 in vivo and in vitro, it shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. This protein also contains 3 tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. This protein may be the target of oncogenic mutations in breast or ovarian cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

BARD1 Gene-Disease associations (from GenCC):

• BARD1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 2 pathogenic, 1 benign (OR vs. background: 8.3); Variant does not impact splicing — splice-hotspot path not applicable
	B2Does not fit gene mode of action		Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context); Activating variant in tumor suppressor gene + same AA change classified germline Benign/Likely Benign — supporting benign evidence (B2, no cancer-type context)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000465.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BARD1 NM_000465.4	MANE Select	c.1613_1614delGTinsAC p.Ser538Asn	missense	N/A	Prot: NP_000456.2 UniProt:
	BARD1 NM_001282543.2		c.1556_1557delGTinsAC p.Ser519Asn	missense	N/A	Prot: NP_001269472.1 UniProt:
	BARD1 NM_001282545.2		c.260_261delGTinsAC p.Ser87Asn	missense	N/A	Prot: NP_001269474.1 UniProt:

BARD1 NM_000465.4

MANE Select

HGVSc / HGVSpc.1613_1614delGTinsACp.Ser538Asn

Exon rankN/A

missense

Prot: NP_000456.2UniProt: Q99728-1

BARD1 NM_001282543.2

HGVSc / HGVSpc.1556_1557delGTinsACp.Ser519Asn

Exon rankN/A

missense

Prot: NP_001269472.1UniProt: Q99728-2

BARD1 NM_001282545.2

HGVSc / HGVSpc.260_261delGTinsACp.Ser87Asn

Exon rankN/A

missense

Prot: NP_001269474.1UniProt: C9IYG1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BARD1 ENST00000260947.9	TSL:1MANE Select	c.1613_1614delGTinsAC p.Ser538Asn	missense	N/A	Prot: ENSP00000260947.4 UniProt:
	BARD1 ENST00000617164.5	TSL:1	c.1556_1557delGTinsAC p.Ser519Asn	missense	N/A	Prot: ENSP00000480470.1 UniProt:
	BARD1 ENST00000613706.5	TSL:1	c.1205_1206delGTinsAC p.Ser402Asn	missense	N/A	Prot: ENSP00000484976.2 UniProt:

BARD1 ENST00000260947.9

TSL:1MANE Select

HGVSc / HGVSpc.1613_1614delGTinsACp.Ser538Asn

Exon rankN/A

missense

Prot: ENSP00000260947.4UniProt: Q99728-1

BARD1 ENST00000617164.5

TSL:1

HGVSc / HGVSpc.1556_1557delGTinsACp.Ser519Asn

Exon rankN/A

missense

Prot: ENSP00000480470.1UniProt: Q99728-2

BARD1 ENST00000613706.5

TSL:1

HGVSc / HGVSpc.1205_1206delGTinsACp.Ser402Asn

Exon rankN/A

missense

Prot: ENSP00000484976.2UniProt: A0A087X2H0

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	1.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 normal (RUO)

1 no calibration

2 assays found for this variant.

Research-use-only (RUO) calibration: 0 functionally abnormal (PS3), 1 functionally normal (BS3).

No calibration: 1 assay (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Nucleotide level

Saturation Genome Editing of BARD1 scores

Saturation Genome Editing of BARD1

• Gene: BARD1
• Assay type: Cell proliferation assay
• Mechanism: Loss of function
• Model system: Immortalized human cells
• Score: 0.00595

Classified as

No clinical calibration. Only research-use-only (RUO) calibrations exist for this assay — they are not reliable evidence; treat them with extreme caution.

BS3 strongFunctionally normalRUO ExCALIBR calibration: BS3 Strong (-6)

Nucleotide level

Saturation Genome Editing of BARD1 scores

Saturation Genome Editing of BARD1

• Gene: BARD1
• Assay type: Cell proliferation assay
• Mechanism: Loss of function
• Model system: Immortalized human cells
• Score: 0.00595

Classified as

normalFunctionally Normal

This score is at approximately the 61th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

hg19: chr2-215617234;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar