rs13389423

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000465.4(BARD1):​c.2183C>T​(p.Ser728Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 9.56
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 Likely_benign. Variant got -4 ACMG points.

BS2
High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BARD1NM_000465.4 linkuse as main transcriptc.2183C>T p.Ser728Phe missense_variant 11/11 ENST00000260947.9 NP_000456.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BARD1ENST00000260947.9 linkuse as main transcriptc.2183C>T p.Ser728Phe missense_variant 11/111 NM_000465.4 ENSP00000260947 P2Q99728-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251340
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135832
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000490
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461886
Hom.:
0
Cov.:
32
AF XY:
0.0000248
AC XY:
18
AN XY:
727242
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:
0.000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000906
AC:
11
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 728 of the BARD1 protein (p.Ser728Phe). This variant is present in population databases (rs13389423, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 479142). 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 testingNeuberg Centre For Genomic Medicine, NCGM-The missense variant p.S728F in BARD1 (NM_000465.4) has been previously reported as a variant of uncertain significance in an individual with breast cancer (Tung J et al). The missense variant c.2183C>T (p.S728F) in BARD1 (NM_000465.4) is observed in 15/30616 (0.049%) alleles from individuals of South Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state.The p.S728F missense variant is predicted to be damaging by both SIFT and PolyPhen2. The serine residue at codon 728 of BARD1 is conserved in all mammalian species. The nucleotide c.2183 in BARD1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 31, 2024This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 728 of the BARD1 protein (p.Ser728Phe).This amino acid position is highly conserved This variant is present in population databases (rs13389423, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 479142). 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. . 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. -
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJan 05, 2024This missense variant replaces serine with phenylalanine at codon 728 of the BARD1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 15/251340 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 04, 2023The p.S728F variant (also known as c.2183C>T), located in coding exon 11 of the BARD1 gene, results from a C to T substitution at nucleotide position 2183. The serine at codon 728 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported as a variant of unknown significance in an individual from a cohort of 488 patients with stages I to III breast cancer (Tung N et al. J Clin Oncol, 2016 May;34:1460-8). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Uncertain
0.089
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.36
T;.;.;.;T;.
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;.
M_CAP
Uncertain
0.23
D
MetaRNN
Uncertain
0.63
D;D;D;D;D;D
MetaSVM
Uncertain
0.24
D
MutationAssessor
Uncertain
2.6
M;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-4.2
D;.;.;.;.;.
REVEL
Uncertain
0.52
Sift
Pathogenic
0.0
D;.;.;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
D;.;.;.;.;.
Vest4
0.69
MutPred
0.23
Loss of disorder (P = 0.0214);.;.;.;.;.;
MVP
0.93
MPC
0.46
ClinPred
0.68
D
GERP RS
5.8
Varity_R
0.51
gMVP
0.71

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: rs13389423; hg19: chr2-215593551; API