rs878853997

Variant names:

• chr2-214780588-TCTC-T
• rs878853997
• NM_000465.4:c.1283_1285delGAG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PM4_Supporting BS2_Supporting

The NM_000465.4(BARD1):​c.1283_1285delGAG​(p.Gly428del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000342 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G428G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BARD1 NM_000465.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.14
• Publications: 1 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000465.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.1283_1285delGAG	p.Gly428del	disruptive_inframe_deletion	Exon 4 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.1226_1228delGAG	p.Gly409del	disruptive_inframe_deletion	Exon 3 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.215+16470_215+16472delGAG		intron	N/A	NP_001269474.1	C9IYG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.1283_1285delGAG	p.Gly428del	disruptive_inframe_deletion	Exon 4 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.1226_1228delGAG	p.Gly409del	disruptive_inframe_deletion	Exon 3 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.906+377_906+379delGAG		intron	N/A	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461684 Hom.: 0 AF XY: 0.00000550 AC XY: 4 AN XY: 727128

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111902

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial cancer of breast (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: -28

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.

Other links and lift over

dbSNP: rs878853997;

hg19: chr2-215645312;