2-214797065-A-T

Position:

• chr2-214797065-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000465.4(BARD1):​c.211T>A​(p.Cys71Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 5.72

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]

BARD1 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.211T>A	p.Cys71Ser	missense_variant	2/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.211T>A	p.Cys71Ser	missense_variant	2/11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2023	The p.C71S variant (also known as c.211T>A), located in coding exon 2 of the BARD1 gene, results from a T to A substitution at nucleotide position 211. The cysteine at codon 71 is replaced by serine, an amino acid with dissimilar properties. This variant was detected in a cohort of 113 Italian non-BRCA patients with a personal and/or familial history of breast cancer, ovarian cancer, and/or pancreatic cancer (Germani A et al. J Clin Med, 2020 Sep;9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 03, 2021	This missense variant replaces cysteine with serine at codon 71 in the RING domain of the BARD1 protein. This variant alters one of the zinc-binding residues of the RING domain that is thought to be important for BARD1 protein function (PMID: 29367421). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer at age 49 with family history of uterine cancer, melanoma, colon cancer and lung cancer (PMID: 32957588). A different nucleotide substitution variant with the same protein consequence (c.212G>C, p.Cys71Ser) has been reported in an individual affected with familial breast cancer (PMID: 31036035). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant affecting the same codon position, p.Cys71Tyr, is known to disrupt BARD1 protein function (PMID: 26350354, 29367421) and is reported as disease-causing (ClinVar variation ID: 978478). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 14, 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. This variant disrupts the p.Cys71 amino acid residue in BARD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26350354, 29367421). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 489667). 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 cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 71 of the BARD1 protein (p.Cys71Ser). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 08, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jul 29, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Benign	0.93
DEOGEN2	Uncertain	0.56	D;.;T;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;D;T;D;.
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;.;.;H;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.5	D;.;.;.;N
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0040	D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.99	D;.;.;.;.
Vest4		0.70
MutPred		0.83		Gain of glycosylation at S72 (P = 0.102);Gain of glycosylation at S72 (P = 0.102);Gain of glycosylation at S72 (P = 0.102);Gain of glycosylation at S72 (P = 0.102);Gain of glycosylation at S72 (P = 0.102);
MVP		1.0
MPC		0.45
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.96
gMVP		0.86

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: rs1060501308; hg19: chr2-215661789;