rs786201905

Variant names:

• chr2-214745778-A-C
• rs786201905
• NM_000465.4:c.1754T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-214745778-A-C
• chr2-214745778-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000465.4(BARD1):​c.1754T>G​(p.Leu585Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. L585V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.13
• 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):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.1754T>G	p.Leu585Arg	missense	Exon 8 of 11	NP_000456.2
	BARD1	NM_001282543.2		c.1697T>G	p.Leu566Arg	missense	Exon 7 of 10	NP_001269472.1
	BARD1	NM_001282545.2		c.401T>G	p.Leu134Arg	missense	Exon 4 of 7	NP_001269474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.1754T>G	p.Leu585Arg	missense	Exon 8 of 11	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.1697T>G	p.Leu566Arg	missense	Exon 7 of 10	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.1346T>G	p.Leu449Arg	missense	Exon 8 of 11	ENSP00000484976.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

African (AFR) AF: 0.0000482 AC: 2 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

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

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Aug 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17550235)

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L585R variant (also known as c.1754T>G), located in coding exon 8 of the BARD1 gene, results from a T to G substitution at nucleotide position 1754. The leucine at codon 585 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Familial cancer of breast Uncertain:1

Jan 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 585 of the BARD1 protein (p.Leu585Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 233952). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.67		Gain of loop (P = 0.0045)
MVP		0.97
MPC		0.34
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.84
Mutation Taster		=40/60	disease causing

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: rs786201905; hg19: chr2-215610502;