chr2-214809479-G-C

Position:

• chr2-214809479-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000465.4(BARD1):​c.91C>G​(p.Arg31Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. R31C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.954

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039484143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.91C>G	p.Arg31Gly	missense_variant	1/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.91C>G	p.Arg31Gly	missense_variant	1/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 76

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 21, 2021

This sequence change replaces arginine with glycine at codon 31 of the BARD1 protein (p.Arg31Gly). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and glycine. 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BARD1-related disease. This variant is not present in population databases (ExAC no frequency). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2022

The p.R31G variant (also known as c.91C>G), located in coding exon 1 of the BARD1 gene, results from a C to G substitution at nucleotide position 91. The arginine at codon 31 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species, and glycine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	0.057
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.4
DANN	Benign	0.61
DEOGEN2	Benign	0.067	T;.;.;.;T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.75	T;T;T;T;T;T;.
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.039	T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.34	N;.;N;.;.;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.56	N;.;.;.;.;.;N
REVEL	Benign	0.15
Sift	Benign	0.74	T;.;.;.;.;.;T
Sift4G	Benign	0.53	T;T;T;T;D;T;D
Polyphen		0.0	B;.;.;.;.;.;.
Vest4		0.10
MutPred		0.28		Loss of MoRF binding (P = 0.0065);Loss of MoRF binding (P = 0.0065);Loss of MoRF binding (P = 0.0065);Loss of MoRF binding (P = 0.0065);Loss of MoRF binding (P = 0.0065);Loss of MoRF binding (P = 0.0065);Loss of MoRF binding (P = 0.0065);
MVP		0.57
MPC		0.096
ClinPred		0.061	T
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.30

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: rs1064795053; hg19: chr2-215674203;