2-214809499-G-C

Position:

• chr2-214809499-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000260947.9(BARD1):​c.71C>G​(p.Pro24Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,722 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BARD1 ENST00000260947.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 2.15

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32656884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.71C>G	p.Pro24Arg	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.71C>G	p.Pro24Arg	missense_variant	1/11	1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000434 AC: 1 AN: 230478 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 127158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453722 Hom.: 0 Cov.: 77 AF XY: 0.00000138 AC XY: 1 AN XY: 722802

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000480 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 18, 2024	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 24 of the BARD1 protein (p.Pro24Arg). This variant is present in population databases (no rsID available, gnomAD 0.001%). 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: 216445). 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 tolerated. 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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 19, 2023	This variant has not been reported in individuals with BARD1-related conditions in the published literature. The frequency of this variant in the general population, 0.0000043 (1/230478 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 04, 2020	This missense variant replaces proline with arginine at codon 24 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 hereditary cancer in the literature. This variant has been identified in 1/230478 chromosomes 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	Jun 05, 2023	The p.P24R variant (also known as c.71C>G), located in coding exon 1 of the BARD1 gene, results from a C to G substitution at nucleotide position 71. The proline at codon 24 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not 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	0.10
BayesDel_addAF	Benign	0.00082	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	T;.;.;.;T;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.85	D;D;D;D;D;D;.
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.5	L;.;L;.;.;L;.
MutationTaster	Benign	0.79	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.5	N;.;.;.;.;.;N
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D;.;.;.;.;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		0.39	B;.;.;.;.;.;.
Vest4		0.37
MutPred		0.22		Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);Gain of MoRF binding (P = 4e-04);
MVP		0.93
MPC		0.082
ClinPred		0.41	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.29

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: rs863224674; hg19: chr2-215674223;