chr2-214809515-C-G

Variant names:

• chr2-214809515-C-G
• rs752514155
• NM_000465.4:c.55G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000465.4(BARD1):​c.55G>C​(p.Glu19Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. E19K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.647
• Publications: 3 publications found

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]

SNHG31 (HGNC:54196): (small nucleolar RNA host gene 31)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094846666).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000465.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.55G>C	p.Glu19Gln	missense	Exon 1 of 11	NP_000456.2
	BARD1	NM_001282543.2		c.55G>C	p.Glu19Gln	missense	Exon 1 of 10	NP_001269472.1
	BARD1	NM_001282545.2		c.55G>C	p.Glu19Gln	missense	Exon 1 of 7	NP_001269474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.55G>C	p.Glu19Gln	missense	Exon 1 of 11	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.55G>C	p.Glu19Gln	missense	Exon 1 of 10	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.55G>C	p.Glu19Gln	missense	Exon 1 of 11	ENSP00000484976.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000463 AC: 1 AN: 215878 AF XY: 0.00

Gnomad AFR exome AF: 0.0000844

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445022 Hom.: 0 Cov.: 74 AF XY: 0.00 AC XY: 0 AN XY: 717954

African (AFR) AF: 0.0000302 AC: 1 AN: 33112

American (AMR) AF: 0.00 AC: 0 AN: 43692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25806

East Asian (EAS) AF: 0.00 AC: 0 AN: 38984

South Asian (SAS) AF: 0.00 AC: 0 AN: 84754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105836

Other (OTH) AF: 0.00 AC: 0 AN: 59754

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial cancer of breast Uncertain:1

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 19 of the BARD1 protein (p.Glu19Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with BARD1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.79
DANN	Benign	0.90
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.090	N
PhyloP100		-0.65
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.25
Sift	Benign	0.46	T
Sift4G	Benign	0.57	T
Polyphen		0.0030	B
Vest4		0.077
MutPred		0.055		Gain of MoRF binding (P = 0.0286)
MVP		0.62
MPC		0.077
ClinPred		0.41	T
GERP RS		-8.0
PromoterAI		-0.020	Neutral
Varity_R		0.071
gMVP		0.39
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs752514155; hg19: chr2-215674239;