rs367890377

Variant names:

• chr2-214781032-G-A
• rs367890377
• NM_000465.4:c.842C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000465.4(BARD1):​c.842C>T​(p.Pro281Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,611,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P281S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:7
• Conservation: PhyloP100: 1.27
• Publications: 3 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.102561414).
• BP6: Variant 2-214781032-G-A is Benign according to our data. Variant chr2-214781032-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 185922.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000191 (29/152158) while in subpopulation AFR AF = 0.0007 (29/41438). AF 95% confidence interval is 0.0005. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 29 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.842C>T	p.Pro281Leu	missense	Exon 4 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.785C>T	p.Pro262Leu	missense	Exon 3 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.215+16029C>T		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.842C>T	p.Pro281Leu	missense	Exon 4 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.785C>T	p.Pro262Leu	missense	Exon 3 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.842C>T	p.Pro281Leu	missense	Exon 4 of 11	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000363 AC: 9 AN: 248168 AF XY: 0.0000224

Gnomad AFR exome AF: 0.000563

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1459064 Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12 AN XY: 725532

African (AFR) AF: 0.000690 AC: 23 AN: 33320

American (AMR) AF: 0.00 AC: 0 AN: 44304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110834

Other (OTH) AF: 0.0000166 AC: 1 AN: 60230

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74324

African (AFR) AF: 0.000700 AC: 29 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	Familial cancer of breast (5)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	1	not provided (2)
-	1	-	BARD1-related cancer predisposition (1)
-	1	-	BARD1-related disorder (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary cancer (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.3
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.066
Sift	Benign	0.078	T
Sift4G	Uncertain	0.025	D
Polyphen		0.076	B
Vest4		0.29
MVP		0.75
MPC		0.079
ClinPred		0.030	T
GERP RS		2.8
Varity_R		0.037
gMVP		0.19
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs367890377; hg19: chr2-215645756;