chr2-214745838-C-A

Variant names:

• chr2-214745838-C-A
• rs146946984
• NM_000465.4:c.1694G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000465.4(BARD1):​c.1694G>T​(p.Arg565Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R565H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.85
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

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.1694G>T	p.Arg565Leu	missense	Exon 8 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.1637G>T	p.Arg546Leu	missense	Exon 7 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.341G>T	p.Arg114Leu	missense	Exon 4 of 7	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.1694G>T	p.Arg565Leu	missense	Exon 8 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.1637G>T	p.Arg546Leu	missense	Exon 7 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.1286G>T	p.Arg429Leu	missense	Exon 8 of 11	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461752 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60388

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
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.025
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.8
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.35
Sift	Benign	0.052	T
Sift4G	Uncertain	0.031	D
Polyphen		0.97	D
Vest4		0.61
MutPred		0.49		Loss of disorder (P = 0.0833)
MVP		0.95
MPC		0.30
ClinPred		0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.20
gMVP		0.61
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs146946984; hg19: chr2-215610562;