Genetic Variant NM_000465.4:c.1613_1614delGTinsAC (chr2-214752510-AC-GT) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is The variant received 4 classification points (ACMG Germline Pathogenicity v2019). PM1PM2

The NM_000465.4(BARD1):c.1613_1614delGTinsAC (p.Ser538Asn) variant causes a missense change. 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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.92

Publications

0 publications found

Variant links:

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

BARD1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000465.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 4 points.

Show applied only (2)

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		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (base 0.0001, raised to 0.000254 by highest known P/LP ClinVar AF 0.000254) — PM2 moderate.

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

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: Q99728-1
BARD1 NM_001282543.2		c.1556_1557delGTinsAC p.Ser519Asn	missense	N/A	Prot: NP_001269472.1 UniProt: Q99728-2
BARD1 NM_001282545.2		c.260_261delGTinsAC p.Ser87Asn	missense	N/A	Prot: NP_001269474.1 UniProt: C9IYG1

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

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: Q99728-1
BARD1 ENST00000617164.5	TSL:1	c.1556_1557delGTinsAC p.Ser519Asn	missense	N/A	Prot: ENSP00000480470.1 UniProt: Q99728-2
BARD1 ENST00000613706.5	TSL:1	c.1205_1206delGTinsAC p.Ser402Asn	missense	N/A	Prot: ENSP00000484976.2 UniProt: A0A087X2H0

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

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence