rs766441081

Positions:

• chr2-214809557-G-A
• chr2-214809557-G-C
• chr2-214809557-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000465.4(BARD1):​c.13C>T​(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,407,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.365

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10863826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.13C>T	p.Arg5Trp	missense_variant	1/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.13C>T	p.Arg5Trp	missense_variant	1/11	1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1407832 Hom.: 0 Cov.: 73 AF XY: 0.00000144 AC XY: 1 AN XY: 696652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.0000342

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 01, 2022	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 5 of the BARD1 protein (p.Arg5Trp). This variant is not present in population databases (gnomAD no frequency). 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: 460705). -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 23, 2023	This missense variant replaces arginine with tryptophan at codon 5 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BARD1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 14, 2022	The p.R5W variant (also known as c.13C>T), located in coding exon 1 of the BARD1 gene, results from a C to T substitution at nucleotide position 13. The arginine at codon 5 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is not conserved on limited sequence alignment. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.;.;.;T;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.0	N;.;N;.;.;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.84	N;.;.;.;.;.;N
REVEL	Benign	0.27
Sift	Uncertain	0.014	D;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.86	P;.;.;.;.;.;.
Vest4		0.18
MutPred		0.14		Loss of glycosylation at P7 (P = 0.2145);Loss of glycosylation at P7 (P = 0.2145);Loss of glycosylation at P7 (P = 0.2145);Loss of glycosylation at P7 (P = 0.2145);Loss of glycosylation at P7 (P = 0.2145);Loss of glycosylation at P7 (P = 0.2145);Loss of glycosylation at P7 (P = 0.2145);
MVP		0.72
MPC		0.089
ClinPred		0.30	T
GERP RS		0.23
Varity_R		0.086
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs766441081; hg19: chr2-215674281;