rs3738888

Variant names:

• chr2-214730440-G-A
• rs3738888
• NM_000465.4:c.1972C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-214730440-G-A
• chr2-214730440-G-C
• chr2-214730440-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000465.4(BARD1):​c.1972C>T​(p.Arg658Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00855 in 1,613,728 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R658H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0073 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (54 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:19
• Conservation: PhyloP100: 5.27
• Publications: 55 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=0.0056836605).
• BP6: Variant 2-214730440-G-A is Benign according to our data. Variant chr2-214730440-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00731 (1113/152168) while in subpopulation EAS AF = 0.00986 (51/5170). AF 95% confidence interval is 0.00787. There are 15 homozygotes in GnomAd4. There are 582 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1113 AD gene.

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.1972C>T	p.Arg658Cys	missense	Exon 10 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.1915C>T	p.Arg639Cys	missense	Exon 9 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.619C>T	p.Arg207Cys	missense	Exon 6 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.1972C>T	p.Arg658Cys	missense	Exon 10 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.1915C>T	p.Arg639Cys	missense	Exon 9 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.1564C>T	p.Arg522Cys	missense	Exon 10 of 11	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 1114 AN: 152050 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00984

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00846

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00843 AC: 2118 AN: 251368 AF XY: 0.00785

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0115

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.00866

Gnomad OTH exome AF: 0.00865

GnomAD4 exome AF: 0.00868 AC: 12682 AN: 1461560 Hom.: 54 Cov.: 30 AF XY: 0.00836 AC XY: 6077 AN XY: 727102

African (AFR) AF: 0.00137 AC: 46 AN: 33470

American (AMR) AF: 0.0112 AC: 500 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26126

East Asian (EAS) AF: 0.0103 AC: 409 AN: 39660

South Asian (SAS) AF: 0.00452 AC: 390 AN: 86252

European-Finnish (FIN) AF: 0.0126 AC: 675 AN: 53400

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.00922 AC: 10254 AN: 1111784

Other (OTH) AF: 0.00664 AC: 401 AN: 60382

GnomAD4 genome AF: 0.00731 AC: 1113 AN: 152168 Hom.: 15 Cov.: 32 AF XY: 0.00782 AC XY: 582 AN XY: 74388

African (AFR) AF: 0.00219 AC: 91 AN: 41524

American (AMR) AF: 0.00667 AC: 102 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00986 AC: 51 AN: 5170

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4816

European-Finnish (FIN) AF: 0.0151 AC: 160 AN: 10580

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00844 AC: 574 AN: 67992

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00821 Hom.: 24

Bravo AF: 0.00749

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00793 AC: 963

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00705

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Familial cancer of breast (6)
-	-	5	not specified (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary cancer (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	not provided (1)
-	1	-	Triple-Negative Breast Cancer Finding (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.3
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.10
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.32
MVP		0.89
MPC		0.20
ClinPred		0.049	T
GERP RS		5.8
PromoterAI		-0.060	Neutral
Varity_R		0.40
gMVP		0.51
Mutation Taster		=75/25	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: rs3738888; hg19: chr2-215595164; COSMIC: COSV53616840;