chr2-214809476-C-T

Position:

• chr2-214809476-C-T

Variant summary

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

The NM_000465.4(BARD1):​c.94G>A​(p.Gly32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.696

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/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.94G>A	p.Gly32Ser	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.94G>A	p.Gly32Ser	missense_variant	1/11	1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457528 Hom.: 0 Cov.: 76 AF XY: 0.00 AC XY: 0 AN XY: 724992

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

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

Aug 28, 2021

This sequence change replaces glycine with serine at codon 32 of the BARD1 protein (p.Gly32Ser). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2023

The p.G32S variant (also known as c.94G>A), located in coding exon 1 of the BARD1 gene, results from a G to A substitution at nucleotide position 94. The glycine at codon 32 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available 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	0.21
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.;.;.;T;.;.
Eigen	Benign	0.093
Eigen_PC	Benign	-0.0079
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;.
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.8	L;.;L;.;.;L;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	N;.;.;.;.;.;N
REVEL	Uncertain	0.29
Sift	Pathogenic	0.0	D;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;T;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.38
MutPred		0.18		Loss of catalytic residue at G32 (P = 0.0058);Loss of catalytic residue at G32 (P = 0.0058);Loss of catalytic residue at G32 (P = 0.0058);Loss of catalytic residue at G32 (P = 0.0058);Loss of catalytic residue at G32 (P = 0.0058);Loss of catalytic residue at G32 (P = 0.0058);Loss of catalytic residue at G32 (P = 0.0058);
MVP		0.99
MPC		0.43
ClinPred		0.92	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.26

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: rs1224914625; hg19: chr2-215674200;