2-214809553-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000465.4(BARD1):c.17A>G(p.Gln6Arg) 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. 14/21 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. Q6K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.284

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_000465.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12535077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.17A>G	p.Gln6Arg	missense_variant	1/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.17A>G	p.Gln6Arg	missense_variant	1/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 74

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

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2022

The p.Q6R variant (also known as c.17A>G), located in coding exon 1 of the BARD1 gene, results from an A to G substitution at nucleotide position 17. The glutamine at codon 6 is replaced by arginine, an amino acid with highly similar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod Pathol, 2016 11;29:1381-1389). This amino acid position is conserved on limited sequence alignment. 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. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 21, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 219745). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 6 of the BARD1 protein (p.Gln6Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	13
Dann	Benign	0.90
DEOGEN2	Benign	0.057	T;.;.;.;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.71	T;T;T;T;T;T;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.69	N;.;N;.;.;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.55	N;.;.;.;.;.;N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;.;.;.;.;.;D
Sift4G	Benign	0.095	T;T;T;D;D;T;D
Polyphen		0.62	P;.;.;.;.;.;.
Vest4		0.18
MutPred		0.13		Gain of methylation at Q6 (P = 0.0473);Gain of methylation at Q6 (P = 0.0473);Gain of methylation at Q6 (P = 0.0473);Gain of methylation at Q6 (P = 0.0473);Gain of methylation at Q6 (P = 0.0473);Gain of methylation at Q6 (P = 0.0473);Gain of methylation at Q6 (P = 0.0473);
MVP		0.67
MPC		0.096
ClinPred		0.29	T
GERP RS		0.23
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.25
gMVP		0.30

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: rs864622229; hg19: chr2-215674277;