chr2-214769266-G-A

Position:

• chr2-214769266-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000465.4(BARD1):​c.1361C>T​(p.Pro454Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 8.89

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1361C>T	p.Pro454Leu	missense_variant	5/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1361C>T	p.Pro454Leu	missense_variant	5/11	1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461420 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 24, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 23, 2021	The p.P454L variant (also known as c.1361C>T), located in coding exon 5 of the BARD1 gene, results from a C to T substitution at nucleotide position 1361. The proline at codon 454 is replaced by leucine, an amino acid with similar properties. This variant was reported in 1/255 ovarian cancer patients but was not observed in 1000 unselected population-based controls or 200 healthy, age-matched, female controls. Using RNA extracted from this patient's serous ovarian tumor, mRNA expression analysis showed an in-frame deletion of exon 5 (Ratajska M et al. Oncol. Rep., 2015 Nov;34:2609-17). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however direct evidence is insufficient at this time (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration as a missense substitution is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 12, 2022	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2016	Variant summary: The BARD1 c.1361C>T (p.Pro454Leu) variant involves the alteration of a conserved nucleotide. This variant is located within the ANK repeats of the protein which suggest possible alteration of the BARD1 structure and/or interactions with other proteins. 4/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant causes a loss of binding motif for splicing enhancer SC15. This variant was found in 1/121022 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188). This variant has been reported in one OvC patient and was shown to cause exon 5 skipping resulting in-frame deletion from c.1315 to c.1395 [r.(=,1315_1395del);p.Gly439_Leu465del], and this this deletion results in disruption of the 1st and 2nd ANK repeat (Ratajska_Oncol Rep_2015). In addition, one clinical diagnostic laboratory classified this variant as VUS, without evidence to independently evaluate. Taken together, because of the absence of clinical information and the lack of functional studies, the variant was classified as VUS-possibly pathogenic until more evidence becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; A functional study demonstrated through mRNA analysis that this variant results in in-frame skipping of exon 5 (Ratajska et al., 2015); Observed in individuals with ovarian or breast cancer as well as at least one unaffected individual in a breast cancer case-control study (Ratajska et al., 2015; Dorling et al., 2021; Suszynska et al., 2022); This variant is associated with the following publications: (PMID: 26329992, 33471991, 37418175, 18480049, 34906988, 32726901, 35650591) -

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 25, 2023	ClinVar contains an entry for this variant (Variation ID: 232097). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26329992). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 454 of the BARD1 protein (p.Pro454Leu). 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. 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. Studies have shown that this missense change is associated with altered splicing resulting in in-frame skipping of exon 5 (PMID: 26329992). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 02, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.39	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.7	D;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.086	T;T
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.48		Loss of disorder (P = 0.0324);.;
MVP		0.88
MPC		0.44
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs772285343; hg19: chr2-215633990;