rs71579841

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_000465.4(BARD1):​c.119C>T​(p.Ala40Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,611,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

4
9
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2

Conservation

PhyloP100: 5.54
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 -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.38985988).
BP6
Variant 2-214809451-G-A is Benign according to our data. Variant chr2-214809451-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142910.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8}.
BS2
High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BARD1NM_000465.4 linkuse as main transcriptc.119C>T p.Ala40Val missense_variant 1/11 ENST00000260947.9 NP_000456.2 Q99728-1A0AVN2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BARD1ENST00000260947.9 linkuse as main transcriptc.119C>T p.Ala40Val missense_variant 1/111 NM_000465.4 ENSP00000260947.4 Q99728-1

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152200
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000292
AC:
7
AN:
239990
Hom.:
0
AF XY:
0.0000531
AC XY:
7
AN XY:
131938
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000878
Gnomad ASJ exome
AF:
0.000102
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000280
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000247
AC:
36
AN:
1459338
Hom.:
0
Cov.:
76
AF XY:
0.0000275
AC XY:
20
AN XY:
726038
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.000422
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000990
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152200
Hom.:
0
Cov.:
34
AF XY:
0.0000538
AC XY:
4
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000691
Hom.:
0
Bravo
AF:
0.0000567
ExAC
AF:
0.0000416
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 22, 2023This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 40 of the BARD1 protein (p.Ala40Val). This variant is present in population databases (rs71579841, gnomAD 0.03%). This missense change has been observed in individual(s) with breast and/or gastric cancer (PMID: 28202063, 30680046). ClinVar contains an entry for this variant (Variation ID: 142910). 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. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 26350354). 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. -
Likely benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Jul 18, 2024This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalAug 22, 2023The BARD1 c.119C>T (p.Ala40Val) missense change has a maximum non-founder subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and a functional assay measuring homology-directed repair (HDR) activity indicates that this variant showed function similar to the wild-type (PMID: 26350354). This variant has been reported in individuals with a personal and/or family history of breast cancer (PMID: 28202063, 32658311). It has also been reported in one individual in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMar 17, 2024- -
not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 12, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 11, 2023In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate homology-directed repair activity comparable to wild-type (PMID: 26350354); Observed in individuals with breast and other cancers, as well as in unaffected controls (PMID: 30680046, 28202063, 28873162, 31036035); This variant is associated with the following publications: (PMID: 11573085, 23056176, 28202063, 26315354, 28873162, 30680046, 30613976, 18480049, 31036035, 26350354) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 21, 2023In the published literature, this variant has been reported in individuals with breast cancer (PMID: 28202063 (2017), 30613976 (2019), 32658311 (2021)), and gastric cancer (PMID: 30680046 (2019)). This variant has also been reported in unaffected individual (PMID: 26315354 (2015)). A homology-directed repair functional assay indicates that this variant is functional (PMID: 26350354 (2015)). The frequency of this variant in the general population, 0.00011 (4/35032 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 09, 2021This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 28, 2023This missense variant replaces alanine with valine at codon 40 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant does not impact homology-directed DNA repair in a cell line-based assay (PMID: 26350354). This variant has been reported in two individuals affected with breast cancer and one individual affected with gastric cancer (PMID: 28202063, 30680046, 30613976) and also in an unaffected individual from an ovarian cancer case-control study (PMID: 26315354). This variant has been identified in 10/271360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 29, 2020Variant summary: BARD1 c.119C>T (p.Ala40Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 246852 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.119C>T has been reported in the literature in individuals affected with breast cancer or gastric cancer (Jalkh_2017, Henn_2019, Rizzolo_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function in vitro (Lee_2015). These results showed no damaging effect of this variant. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Benign
0.010
T
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.13
T;.;.;.;T;.;.
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.92
D;D;D;D;D;D;.
M_CAP
Pathogenic
0.86
D
MetaRNN
Benign
0.39
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.46
D
MutationAssessor
Benign
1.8
L;.;L;.;.;L;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-2.1
N;.;.;.;.;.;N
REVEL
Uncertain
0.45
Sift
Uncertain
0.0040
D;.;.;.;.;.;D
Sift4G
Pathogenic
0.0
D;T;D;T;D;D;D
Polyphen
1.0
D;.;.;.;.;.;.
Vest4
0.50
MVP
0.98
MPC
0.43
ClinPred
0.48
T
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.66
gMVP
0.56

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs71579841; hg19: chr2-215674175; COSMIC: COSV53612987; COSMIC: COSV53612987; API