rs2229571

Variant names:

• chr2-214780740-C-G
• rs2229571
• NM_000465.4:c.1134G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-214780740-C-G
• chr2-214780740-C-T
• chr2-214780740-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000465.4(BARD1):​c.1134G>C​(p.Arg378Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,613,584 control chromosomes in the GnomAD database, including 277,240 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R378K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.53 (22198 hom., cov: 31)
  • Exomes 𝑓: 0.59 (255042 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.395
• Publications: 95 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.4821157E-6).
• BP6: Variant 2-214780740-C-G is Benign according to our data. Variant chr2-214780740-C-G is described in ClinVar as Benign. ClinVar VariationId is 142769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

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.1134G>C	p.Arg378Ser	missense	Exon 4 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.1077G>C	p.Arg359Ser	missense	Exon 3 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.215+16321G>C		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.1134G>C	p.Arg378Ser	missense	Exon 4 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.1077G>C	p.Arg359Ser	missense	Exon 3 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.906+228G>C		intron	N/A	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80463 AN: 151750 Hom.: 22188 Cov.: 31

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.470

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.682

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.538

GnomAD2 exomes AF: 0.544 AC: 136602 AN: 251286 AF XY: 0.549

Gnomad AFR exome AF: 0.398

Gnomad AMR exome AF: 0.413

Gnomad ASJ exome AF: 0.585

Gnomad EAS exome AF: 0.365

Gnomad FIN exome AF: 0.693

Gnomad NFE exome AF: 0.617

Gnomad OTH exome AF: 0.554

GnomAD4 exome AF: 0.586 AC: 856788 AN: 1461716 Hom.: 255042 Cov.: 77 AF XY: 0.585 AC XY: 425316 AN XY: 727144

African (AFR) AF: 0.393 AC: 13172 AN: 33476

American (AMR) AF: 0.420 AC: 18756 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 15059 AN: 26134

East Asian (EAS) AF: 0.357 AC: 14161 AN: 39690

South Asian (SAS) AF: 0.486 AC: 41909 AN: 86258

European-Finnish (FIN) AF: 0.692 AC: 36953 AN: 53418

Middle Eastern (MID) AF: 0.527 AC: 3038 AN: 5768

European-Non Finnish (NFE) AF: 0.611 AC: 679690 AN: 1111886

Other (OTH) AF: 0.564 AC: 34050 AN: 60382

GnomAD4 genome AF: 0.530 AC: 80489 AN: 151868 Hom.: 22198 Cov.: 31 AF XY: 0.529 AC XY: 39307 AN XY: 74246

African (AFR) AF: 0.398 AC: 16490 AN: 41388

American (AMR) AF: 0.469 AC: 7156 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2035 AN: 3472

East Asian (EAS) AF: 0.373 AC: 1918 AN: 5142

South Asian (SAS) AF: 0.482 AC: 2321 AN: 4818

European-Finnish (FIN) AF: 0.682 AC: 7191 AN: 10538

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.612 AC: 41559 AN: 67940

Other (OTH) AF: 0.537 AC: 1133 AN: 2110

Alfa AF: 0.586 Hom.: 19838

Bravo AF: 0.501

TwinsUK AF: 0.604 AC: 2241

ALSPAC AF: 0.611 AC: 2354

ESP6500AA AF: 0.397 AC: 1750

ESP6500EA AF: 0.601 AC: 5167

ExAC AF: 0.548 AC: 66575

Asia WGS AF: 0.439 AC: 1528 AN: 3478

EpiCase AF: 0.595

EpiControl AF: 0.591

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Familial cancer of breast (6)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	not provided (2)
-	-	1	BARD1-related cancer predisposition (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	1.4
DANN	Benign	0.90
DEOGEN2	Benign	0.061	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0000055	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.40
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.11
Sift	Benign	0.17	T
Sift4G	Uncertain	0.059	T
Polyphen		0.031	B
Vest4		0.055
MutPred		0.13		Loss of MoRF binding (P = 0.0074)
MPC		0.11
ClinPred		0.0027	T
GERP RS		-1.0
Varity_R		0.087
gMVP		0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs2229571; hg19: chr2-215645464; COSMIC: COSV53612030; COSMIC: COSV53612030;