2-214728537-C-CTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000465.4(BARD1):​c.*136_*138dupAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 39 hom., cov: 0)
Exomes 𝑓: 0.023 ( 7 hom. )
Failed GnomAD Quality Control

Consequence

BARD1
NM_000465.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.392

Publications

1 publications found
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]
BARD1 Gene-Disease associations (from GenCC):
  • breast cancer
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • hereditary breast carcinoma
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
  • familial ovarian cancer
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • hereditary nonpolyposis colon cancer
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP6
Variant 2-214728537-C-CTTT is Benign according to our data. Variant chr2-214728537-C-CTTT is described in ClinVar as [Likely_benign]. Clinvar id is 801874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BARD1NM_000465.4 linkc.*136_*138dupAAA 3_prime_UTR_variant Exon 11 of 11 ENST00000260947.9 NP_000456.2 Q99728-1A0AVN2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BARD1ENST00000260947.9 linkc.*136_*138dupAAA 3_prime_UTR_variant Exon 11 of 11 1 NM_000465.4 ENSP00000260947.4 Q99728-1

Frequencies

GnomAD3 genomes
AF:
0.0182
AC:
2620
AN:
143954
Hom.:
39
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.00564
Gnomad AMI
AF:
0.0487
Gnomad AMR
AF:
0.0131
Gnomad ASJ
AF:
0.0371
Gnomad EAS
AF:
0.00160
Gnomad SAS
AF:
0.0146
Gnomad FIN
AF:
0.0184
Gnomad MID
AF:
0.0227
Gnomad NFE
AF:
0.0267
Gnomad OTH
AF:
0.0218
GnomAD4 exome
AF:
0.0228
AC:
10091
AN:
441932
Hom.:
7
Cov.:
6
AF XY:
0.0226
AC XY:
5176
AN XY:
229074
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0160
AC:
190
AN:
11894
American (AMR)
AF:
0.0156
AC:
232
AN:
14908
Ashkenazi Jewish (ASJ)
AF:
0.0279
AC:
343
AN:
12272
East Asian (EAS)
AF:
0.00573
AC:
155
AN:
27030
South Asian (SAS)
AF:
0.0244
AC:
818
AN:
33554
European-Finnish (FIN)
AF:
0.0262
AC:
639
AN:
24382
Middle Eastern (MID)
AF:
0.0152
AC:
35
AN:
2304
European-Non Finnish (NFE)
AF:
0.0245
AC:
7146
AN:
291462
Other (OTH)
AF:
0.0221
AC:
533
AN:
24126
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.338
Heterozygous variant carriers
0
664
1328
1992
2656
3320
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
124
248
372
496
620
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0182
AC:
2618
AN:
143982
Hom.:
39
Cov.:
0
AF XY:
0.0168
AC XY:
1169
AN XY:
69640
show subpopulations
African (AFR)
AF:
0.00563
AC:
222
AN:
39442
American (AMR)
AF:
0.0131
AC:
191
AN:
14556
Ashkenazi Jewish (ASJ)
AF:
0.0371
AC:
127
AN:
3420
East Asian (EAS)
AF:
0.00160
AC:
8
AN:
4986
South Asian (SAS)
AF:
0.0147
AC:
67
AN:
4570
European-Finnish (FIN)
AF:
0.0184
AC:
141
AN:
7678
Middle Eastern (MID)
AF:
0.0211
AC:
6
AN:
284
European-Non Finnish (NFE)
AF:
0.0267
AC:
1769
AN:
66162
Other (OTH)
AF:
0.0217
AC:
43
AN:
1980
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
111
222
334
445
556
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
34
68
102
136
170
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0279
Hom.:
739

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Aug 14, 2019
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Familial cancer of breast Benign:1
May 28, 2019
Mendelics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
-0.39
Mutation Taster
=100/0
polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs113789798; hg19: chr2-215593261; API