2-214728537-C-CTTT

Variant names:

• chr2-214728537-C-CTTT
• rs113789798
• ENST00000471590.5:n.805_807dupAAA

Variant summary

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

The ENST00000471590.5(BARD1):​n.805_807dupAAA variant causes a non coding transcript exon 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 ENST00000471590.5 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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: 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
BARD1	NM_000465.4	c.*136_*138dupAAA		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.*136_*138dupAAA		3_prime_UTR_variant	Exon 11 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2620 AN: 143954 Hom.: 39 Cov.: 0

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

⚠️ 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.

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

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

Alfa AF: 0.0279 Hom.: 739

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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

Other links and lift over

dbSNP: rs113789798; hg19: chr2-215593261;