rs111367604

chr2-214728927-C-Achr2-214728927-C-Gchr2-214728927-C-T

Variant summary

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

The NM_000465.4(BARD1):c.2083G>T(p.Val695Phe) 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. 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. V695I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62

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=0.32958817).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.2083G>T	p.Val695Phe	missense_variant	11/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.2083G>T	p.Val695Phe	missense_variant	11/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2016

This variant is denoted BARD1 c.2083G>T at the cDNA level, p.Val695Phe (V695F) at the protein level, and results in the change of a Valine to a Phenylalanine (GTC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Val695Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Phenylalanine differ in some properties, this is considered a semi-conservative amino acid substitution. BARD1 Val695Phe occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the BRCT2 domain (UniProt). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may increase a cryptic splice acceptor site for exon 11 and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BARD1 Val695Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;.;.;T;.
Eigen	Benign	0.040
Eigen_PC	Benign	-0.054
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;.
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.9	L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.6	D;.;.;.;.;.
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D;.;.;.;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.29
MutPred		0.47		Loss of loop (P = 0.0374);.;.;.;.;.;
MVP		0.82
MPC		0.47
ClinPred		0.96	D
GERP RS		3.1
Varity_R		0.50
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs111367604; hg19: chr2-215593651;