chr2-214730446-C-G

Variant names:

• chr2-214730446-C-G
• rs766781362
• NM_000465.4:c.1966G>C

Variant summary

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

The NM_000465.4(BARD1):​c.1966G>C​(p.Gly656Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.51

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1966G>C	p.Gly656Arg	missense_variant	Exon 10 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1966G>C	p.Gly656Arg	missense_variant	Exon 10 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Sep 11, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BARD1 c.1966G>C at the cDNA level, p.Gly656Arg (G656R) at the protein level, and results in the change of a Glycine to an Arginine (GGT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Gly656Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Gly656Arg occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BARD1 Gly656Arg is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BARD1 p.Gly656Arg variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or Zhejiang University Database. The variant was identified in dbSNP (ID: rs766781362) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by GeneDx). The variant was identified in control databases in 1 of 246140 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111616 chromosomes (freq: 0.000009), but not observed in the African, “Other”, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Gly656 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 656 of the BARD1 protein (p.Gly656Arg). This variant is present in population databases (rs766781362, gnomAD 0.0009%). 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: 245820). 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. Experimental studies have shown that this missense change affects BARD1 function (PMID: 30925164). 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D;.;.;.;T;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.6	D;.;.;.;.;.;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.89
MutPred		0.42		Gain of glycosylation at P657 (P = 0.0663);.;.;.;.;.;.;
MVP		0.80
MPC		0.47
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.89

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: rs766781362; hg19: chr2-215595170;