2-214728537-CTTTTTT-CTTTTTTTTTT

Variant names:

• chr2-214728537-C-CTTTT
• rs113789798
• ENST00000471590.5:n.804_807dupAAAA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000465.4(BARD1):​c.*135_*138dupAAAA 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00083 (1 hom.)
• Consequence: BARD1 NM_000465.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.392
• Publications: 1 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-214728537-C-CTTTT is Benign according to our data. Variant chr2-214728537-C-CTTTT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 369328.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.*135_*138dupAAAA		3_prime_UTR_variant	Exon 11 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.*135_*138dupAAAA		3_prime_UTR_variant	Exon 11 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.0000208 AC: 3 AN: 143986 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

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: 0.0000453

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000833 AC: 370 AN: 444024 Hom.: 1 Cov.: 6 AF XY: 0.000839 AC XY: 193 AN XY: 230172

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000335 AC: 4 AN: 11944

American (AMR) AF: 0.000735 AC: 11 AN: 14976

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 14 AN: 12364

East Asian (EAS) AF: 0.000295 AC: 8 AN: 27110

South Asian (SAS) AF: 0.00119 AC: 40 AN: 33712

European-Finnish (FIN) AF: 0.000654 AC: 16 AN: 24480

Middle Eastern (MID) AF: 0.000433 AC: 1 AN: 2312

European-Non Finnish (NFE) AF: 0.000884 AC: 259 AN: 292892

Other (OTH) AF: 0.000701 AC: 17 AN: 24234

⚠️ 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.

GnomAD4 genome AF: 0.0000208 AC: 3 AN: 143986 Hom.: 0 Cov.: 0 AF XY: 0.0000287 AC XY: 2 AN XY: 69594

African (AFR) AF: 0.00 AC: 0 AN: 39370

American (AMR) AF: 0.00 AC: 0 AN: 14546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 5002

South Asian (SAS) AF: 0.00 AC: 0 AN: 4596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000453 AC: 3 AN: 66190

Other (OTH) AF: 0.00 AC: 0 AN: 1970

Alfa AF: 0.00 Hom.: 739

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast neoplasm Uncertain:1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely 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

Splicing

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

Other links and lift over

dbSNP: rs113789798; hg19: chr2-215593261;