rs1553612188

Positions:

• chr2-214728917-C-A
• chr2-214728917-C-G
• chr2-214728917-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000465.4(BARD1):​c.2093G>T​(p.Gly698Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G698A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.54

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20843062).
• BP6: Variant 2-214728917-C-A is Benign according to our data. Variant chr2-214728917-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 962573.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.2093G>T	p.Gly698Val	missense_variant	11/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.2093G>T	p.Gly698Val	missense_variant	11/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 16, 2019

This sequence change replaces glycine with valine at codon 698 of the BARD1 protein (p.Gly698Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with BARD1-related conditions. This variant is not present in population databases (ExAC no frequency). -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.58	D;.;.;.;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.3	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.1	D;.;.;.;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.0070	D;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;D;D
Polyphen		0.98	D;.;.;.;.;.
Vest4		0.21
MutPred		0.51		Loss of disorder (P = 0.0597);.;.;.;.;.;
MVP		0.77
MPC		0.29
ClinPred		0.85	D
GERP RS		3.0
Varity_R		0.56
gMVP		0.76

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: rs1553612188; hg19: chr2-215593641;