chr2-214781152-G-C

Variant names:

• chr2-214781152-G-C
• rs3738885
• NM_000465.4:c.722C>G

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.722C>G​(p.Ser241Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000603 in 1,576,586 control chromosomes in the GnomAD database, including 19 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. S241F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (19 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 3.68
• Publications: 16 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=0.00973776).
• BP6: Variant 2-214781152-G-C is Benign according to our data. Variant chr2-214781152-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136497.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 = 0.000269 (41/152290) while in subpopulation EAS AF = 0.00792 (41/5176). AF 95% confidence interval is 0.006. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 41 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.722C>G	p.Ser241Cys	missense	Exon 4 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.665C>G	p.Ser222Cys	missense	Exon 3 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.215+15909C>G		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.722C>G	p.Ser241Cys	missense	Exon 4 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.665C>G	p.Ser222Cys	missense	Exon 3 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.722C>G	p.Ser241Cys	missense	Exon 4 of 11	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00790

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000134 AC: 29 AN: 216258 AF XY: 0.000112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000198

GnomAD4 exome AF: 0.000639 AC: 910 AN: 1424296 Hom.: 19 Cov.: 34 AF XY: 0.000627 AC XY: 443 AN XY: 706110

African (AFR) AF: 0.00 AC: 0 AN: 31420

American (AMR) AF: 0.00 AC: 0 AN: 36226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23802

East Asian (EAS) AF: 0.0228 AC: 902 AN: 39484

South Asian (SAS) AF: 0.00 AC: 0 AN: 78000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5548

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099058

Other (OTH) AF: 0.000136 AC: 8 AN: 58636

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74468

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00792 AC: 41 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Familial cancer of breast (5)
-	-	5	not specified (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	not provided (2)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.35
MVP		0.94
MPC		0.35
ClinPred		0.12	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.22
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs3738885; hg19: chr2-215645876;