2-214809463-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000260947.9(BARD1):ā€‹c.107A>Cā€‹(p.His36Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H36D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

BARD1
ENST00000260947.9 missense

Scores

1
12
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.878
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BARD1NM_000465.4 linkuse as main transcriptc.107A>C p.His36Pro missense_variant 1/11 ENST00000260947.9 NP_000456.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BARD1ENST00000260947.9 linkuse as main transcriptc.107A>C p.His36Pro missense_variant 1/111 NM_000465.4 ENSP00000260947 P2Q99728-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1458832
Hom.:
0
Cov.:
76
AF XY:
0.00
AC XY:
0
AN XY:
725758
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 04, 2024This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 36 of the BARD1 protein (p.His36Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 233317). 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. -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 15, 2024- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 07, 2017This variant is denoted BARD1 c.107A>C at the cDNA level, p.His36Pro (H36P) at the protein level, and results in the change of a Histidine to a Proline (CAC>CCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 His36Pro was not observed in large population cohorts (Lek 2016). Since Histidine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 His36Pro is located in the BRCA1 interaction domain (Fox 2008). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BARD1 His36Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 10, 2022The p.H36P variant (also known as c.107A>C), located in coding exon 1 of the BARD1 gene, results from an A to C substitution at nucleotide position 107. The histidine at codon 36 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.067
T
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
26
DANN
Uncertain
0.98
DEOGEN2
Benign
0.26
T;.;.;.;T;.;.
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.25
FATHMM_MKL
Benign
0.40
N
LIST_S2
Uncertain
0.87
D;D;D;D;D;D;.
M_CAP
Pathogenic
0.90
D
MetaRNN
Uncertain
0.46
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.064
D
MutationAssessor
Benign
1.8
L;.;L;.;.;L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-3.2
D;.;.;.;.;.;N
REVEL
Uncertain
0.36
Sift
Uncertain
0.022
D;.;.;.;.;.;D
Sift4G
Uncertain
0.017
D;T;D;T;D;D;D
Polyphen
0.99
D;.;.;.;.;.;.
Vest4
0.54
MutPred
0.16
Gain of glycosylation at H36 (P = 0.0246);Gain of glycosylation at H36 (P = 0.0246);Gain of glycosylation at H36 (P = 0.0246);Gain of glycosylation at H36 (P = 0.0246);Gain of glycosylation at H36 (P = 0.0246);Gain of glycosylation at H36 (P = 0.0246);Gain of glycosylation at H36 (P = 0.0246);
MVP
0.98
MPC
0.46
ClinPred
0.98
D
GERP RS
4.0
Varity_R
0.90
gMVP
0.46

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs864622635; hg19: chr2-215674187; API