chr2-214809500-G-C

Position:

• chr2-214809500-G-C

Variant summary

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

The NM_000465.4(BARD1):​c.70C>G​(p.Pro24Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,451,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. P24R) has been classified 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, single submitter U:2
• Conservation: PhyloP100: 0.990

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=0.27767327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.70C>G	p.Pro24Ala	missense_variant	1/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.70C>G	p.Pro24Ala	missense_variant	1/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1451244 Hom.: 0 Cov.: 77 AF XY: 0.00000277 AC XY: 2 AN XY: 721392

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: 0.0000667

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

BARD1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

The BARD1 c.70C>G variant is predicted to result in the amino acid substitution p.Pro24Ala. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/1757163/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2020

The p.P24A variant (also known as c.70C>G), located in coding exon 1 of the BARD1 gene, results from a C to G substitution at nucleotide position 70. The proline at codon 24 is replaced by alanine, an amino acid with highly 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	0.056
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T;.;.;.;T;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;.
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.5	L;.;L;.;.;L;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.4	N;.;.;.;.;.;N
REVEL	Benign	0.28
Sift	Uncertain	0.028	D;.;.;.;.;.;D
Sift4G	Uncertain	0.032	D;T;D;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.;.
Vest4		0.27
MutPred		0.12		Gain of MoRF binding (P = 0.0535);Gain of MoRF binding (P = 0.0535);Gain of MoRF binding (P = 0.0535);Gain of MoRF binding (P = 0.0535);Gain of MoRF binding (P = 0.0535);Gain of MoRF binding (P = 0.0535);Gain of MoRF binding (P = 0.0535);
MVP		0.94
MPC		0.074
ClinPred		0.20	T
GERP RS		3.1
Varity_R		0.073
gMVP		0.25

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: rs1048108; hg19: chr2-215674224;