2-214728894-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000465.4(BARD1):​c.2116A>G​(p.Lys706Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:3

Conservation

PhyloP100: 5.46
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.18410087).
BP6
Variant 2-214728894-T-C is Benign according to our data. Variant chr2-214728894-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127730.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=3}.
BS2
High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BARD1NM_000465.4 linkc.2116A>G p.Lys706Glu missense_variant 11/11 ENST00000260947.9 NP_000456.2 Q99728-1A0AVN2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BARD1ENST00000260947.9 linkc.2116A>G p.Lys706Glu missense_variant 11/111 NM_000465.4 ENSP00000260947.4 Q99728-1

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152210
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000995
AC:
25
AN:
251320
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135812
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000220
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000155
AC:
226
AN:
1461874
Hom.:
0
Cov.:
32
AF XY:
0.000143
AC XY:
104
AN XY:
727236
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000199
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000211
Hom.:
0
Bravo
AF:
0.000102
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 23, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 706 of the BARD1 protein (p.Lys706Glu). This variant is present in population databases (rs149262370, gnomAD 0.02%). This missense change has been observed in individual(s) with BARD1-related conditions (PMID: 26315354, 27443514, 29596542, 32268276, 33118316). ClinVar contains an entry for this variant (Variation ID: 127730). 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 tolerated. 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 testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalOct 18, 2023The BARD1 c.2116A>G (p.Lys706Glu) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in a large case-control study of breast cancer in 9 of 60466 cases and 6 of 53461 controls (PMID: 33471991), and in a small case-control study of epithelial ovarian cancer in 2 of 3236 cases and 1 of 3431 controls (PMID: 26315354). It has been reported in other individuals with breast, colorectal, and endometrial cancer (25186627, 27443514, 29945567, 32885271). This variant is present in two individuals 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 24, 2024- -
Likely benign, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Jul 29, 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]. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 16, 2016- -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Dec 16, 2021- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 21, 2018This 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. -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 21, 2021In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26315354, 27443514, 25230021, 29596542, 25186627, 33875564) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoOct 28, 2024The BARD1 c.2116A>G (p.Lys706Glu) variant has been reported in the published literature in individuals with breast cancer (PMID: 25186627 (2015)), endometrial cancer (PMID: 27443514 (2016)), ovarian cancer (PMID: 26315354 (2015)), colorectal cancer (PMID: 33118316 (2020)), and in an individual with multiple primary cancers (PMID: 34326862 (2021)). This variant was observed in numerous breast cancer cases as well as in reportedly healthy individuals in a case-control study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.0002 (26/129080 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 18, 2024Variant summary: BARD1 c.2116A>G (p.Lys706Glu) results in a conservative amino acid change located in the second BRCT domain (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 258182 control chromosomes, predominantly at a frequency of 0.00022 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BARD1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.0001 vs 0.00025), allowing no conclusion about variant significance. c.2116A>G has been reported in the literature in individuals affected with endometrial-, breast- or ovarian cancer (Ring 2016, Tung 2014, Ramus 2015, Bhai_2021), however without strong evidence for causality, and it was also found in controls (Ramus 2015). Furthermore, the variant was reported in 2/7325 European American women, who are older than age 70 years, and who have never had cancer (in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRIP1 c.2392C>T (p.Arg798X) in our internal database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 26315354, 27443514, 25186627). ClinVar contains an entry for this variant (Variation ID: 127730). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Familial adenomatous polyposis 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalMar 08, 2023The BARD1 c.2116A>G (p.Lys706Glu) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in a large case-control study of breast cancer in 9 of 60466 cases and 6 of 53461 controls (PMID: 33471991), and in a small case-control study of epithelial ovarian cancer in 2 of 3236 cases and 1 of 3431 controls (PMID: 26315354). It has been reported in other individuals with breast, colorectal, and endometrial cancer (25186627, 27443514, 29945567, 32885271). This variant is present in two individuals 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. -
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The BARD1 p.Lys706Glu variant was identified in 3 of 7234 proband chromosomes (frequency: 0.0004) from individuals or families with epithelial ovarian cancer or endometrial carcinoma and was present in 1 of 6862 control chromosomes (frequency: 0.0002) from healthy individuals (Ramus 2015, Ring 2016). The variant was identified in dbSNP (ID: rs149262370) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and two clinical laboratories), MutDB, and in Zhejiang University databases (1x). The variant was identified in control databases in 26 of 277080 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24032 chromosomes (freq: 0.00004), European in 25 of 126608 chromosomes (freq: 0.0002), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Lys706 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.048
T;.;.;.;T;.
Eigen
Benign
0.17
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;.
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.18
T;T;T;T;T;T
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
1.1
L;.;.;.;.;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.40
N;.;.;.;.;.
REVEL
Benign
0.077
Sift
Benign
0.20
T;.;.;.;.;.
Sift4G
Benign
0.080
T;T;T;T;T;T
Polyphen
0.79
P;.;.;.;.;.
Vest4
0.21
MVP
0.89
MPC
0.23
ClinPred
0.14
T
GERP RS
4.6
Varity_R
0.66
gMVP
0.52

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: rs149262370; hg19: chr2-215593618; API