2-214809526-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000465.4(BARD1):c.44G>C(p.Arg15Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R15C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.922

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 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_000465.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.44G>C	p.Arg15Pro	missense_variant	1/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.44G>C	p.Arg15Pro	missense_variant	1/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 74

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2021

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 15 of the BARD1 protein (p.Arg15Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.;.;.;T;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;.
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.075	D
MutationAssessor	Benign	1.6	L;.;L;.;.;L;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.8	N;.;.;.;.;.;N
REVEL	Uncertain	0.48
Sift	Benign	0.062	T;.;.;.;.;.;D
Sift4G	Benign	0.13	T;T;T;D;D;T;D
Polyphen		0.98	D;.;.;.;.;.;.
Vest4		0.33
MutPred		0.18		Loss of MoRF binding (P = 0.0051);Loss of MoRF binding (P = 0.0051);Loss of MoRF binding (P = 0.0051);Loss of MoRF binding (P = 0.0051);Loss of MoRF binding (P = 0.0051);Loss of MoRF binding (P = 0.0051);Loss of MoRF binding (P = 0.0051);
MVP		0.97
MPC		0.48
ClinPred		0.94	D
GERP RS		3.1
Varity_R		0.46
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-215674250;