chr2-214752511-C-T

Variant names:

• chr2-214752511-C-T
• rs370771157
• NM_000465.4:c.1613G>A
• BARD1 p.Ser538Asn

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM1PM2_SupportingBP4_ModerateBP6

The NM_000465.4(BARD1):c.1613G>A (p.Ser538Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000985 (AC=159) in the gnomAD database across 1,613,658 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000113. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S538R: Uncertain_significance (ClinVar VariationId 3240860, 2 stars); p.S538= (synonymous): Benign/Likely_benign (ClinVar VariationId 629875, 2 stars)

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:3
• Conservation: PhyloP100: 1.92
• Publications: 5 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 1 benign (OR vs. background: 8.3).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000113 — borderline rare for AD/XL gene (base 0.0001, raised to 0.000254 by highest known P/LP ClinVar AF 0.000254) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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.1613G>A p.Ser538Asn	missense	Exon 7 of 11	Prot: NP_000456.2 UniProt:
	BARD1 NM_001282543.2		c.1556G>A p.Ser519Asn	missense	Exon 6 of 10	Prot: NP_001269472.1 UniProt:
	BARD1 NM_001282545.2		c.260G>A p.Ser87Asn	missense	Exon 3 of 7	Prot: NP_001269474.1 UniProt:

BARD1 NM_000465.4

MANE Select

HGVSc / HGVSpc.1613G>Ap.Ser538Asn

Exon rankExon 7 of 11

missense

Prot: NP_000456.2UniProt: Q99728-1

BARD1 NM_001282543.2

HGVSc / HGVSpc.1556G>Ap.Ser519Asn

Exon rankExon 6 of 10

missense

Prot: NP_001269472.1UniProt: Q99728-2

BARD1 NM_001282545.2

HGVSc / HGVSpc.260G>Ap.Ser87Asn

Exon rankExon 3 of 7

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.1613G>A p.Ser538Asn	missense	Exon 7 of 11	Prot: ENSP00000260947.4 UniProt:
	BARD1 ENST00000617164.5	TSL:1	c.1556G>A p.Ser519Asn	missense	Exon 6 of 10	Prot: ENSP00000480470.1 UniProt:
	BARD1 ENST00000613706.5	TSL:1	c.1205G>A p.Ser402Asn	missense	Exon 7 of 11	Prot: ENSP00000484976.2 UniProt:

BARD1 ENST00000260947.9

TSL:1MANE Select

HGVSc / HGVSpc.1613G>Ap.Ser538Asn

Exon rankExon 7 of 11

missense

Prot: ENSP00000260947.4UniProt: Q99728-1

BARD1 ENST00000617164.5

TSL:1

HGVSc / HGVSpc.1556G>Ap.Ser519Asn

Exon rankExon 6 of 10

missense

Prot: ENSP00000480470.1UniProt: Q99728-2

BARD1 ENST00000613706.5

TSL:1

HGVSc / HGVSpc.1205G>Ap.Ser402Asn

Exon rankExon 7 of 11

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000329	AC:5	Hom:0	AN:152166	Cov:32
GnomAD2 exomes	AF: 0.0000199	AC:5	Hom:	AN:251332	Cov:
GnomAD4 exome	AF: 0.000105	AC:154	Hom:0	AN:1461492	Cov:31
GnomAD4 genome	AF: 0.0000329	AC:5	Hom:0	AN:152166	Cov:32
TOPMed (Bravo)	AF: 0.0000227	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000487	AC:3	Hom:0	AN:61650	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000704	2	28418	0.000139	4	28844
Epi25(Epilepsy)	0.0000477	2	41954	0.0000150	1	66882
SCHEMA(Schizophrenia)	0.0000246	3	121880	0.0000367	7	190692

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Familial cancer of breast (4)
-	1	2	Hereditary cancer-predisposing syndrome (3)
-	3	-	not provided (3)
-	1	-	BARD1-related cancer predisposition (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.6
DANN	Benign	0.18
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.066	N
FuncVEP CTI	Benign	0.00028
GPN-Star LLR	N/A	6.6
GPN-Star score	N/A	2.6
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.82	T
Mutation Taster	N/A	91/9	polymorphism
MutationAssessor	Benign	-2.1	N
PhyloP100	Benign	1.9
popEVE	Benign	-3.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.13
Sift	Benign	0.76	T
Sift4G	Benign	0.57	T
Varity_R	N/A	0.061
VESM-3B	Benign	-4.5

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

dbSNP: rs370771157;

hg19: chr2-215617235;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar