rs2070093

Variant names:

• chr2-214767532-A-G
• rs2070093
• NM_000465.4:c.1518T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-214767532-A-G
• chr2-214767532-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000465.4(BARD1):​c.1518T>C​(p.His506His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 1,612,710 control chromosomes in the GnomAD database, including 522,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (44244 hom., cov: 32)
  • Exomes 𝑓: 0.81 (478353 hom.)
• Consequence: BARD1 NM_000465.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.241
• Publications: 42 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-214767532-A-G is Benign according to our data. Variant chr2-214767532-A-G is described in ClinVar as Benign. ClinVar VariationId is 183704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.241 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1518T>C	p.His506His	synonymous_variant	Exon 6 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1518T>C	p.His506His	synonymous_variant	Exon 6 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114859 AN: 151980 Hom.: 44222 Cov.: 32

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.829

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.840

Gnomad FIN AF: 0.899

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.737

GnomAD2 exomes AF: 0.817 AC: 205304 AN: 251312 AF XY: 0.819

Gnomad AFR exome AF: 0.597

Gnomad AMR exome AF: 0.816

Gnomad ASJ exome AF: 0.827

Gnomad EAS exome AF: 0.954

Gnomad FIN exome AF: 0.893

Gnomad NFE exome AF: 0.806

Gnomad OTH exome AF: 0.793

GnomAD4 exome AF: 0.808 AC: 1179667 AN: 1460612 Hom.: 478353 Cov.: 54 AF XY: 0.810 AC XY: 588295 AN XY: 726672

African (AFR) AF: 0.584 AC: 19504 AN: 33410

American (AMR) AF: 0.808 AC: 36112 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 21520 AN: 26124

East Asian (EAS) AF: 0.940 AC: 37320 AN: 39692

South Asian (SAS) AF: 0.841 AC: 72547 AN: 86228

European-Finnish (FIN) AF: 0.891 AC: 47598 AN: 53406

Middle Eastern (MID) AF: 0.756 AC: 4358 AN: 5766

European-Non Finnish (NFE) AF: 0.804 AC: 892986 AN: 1110916

Other (OTH) AF: 0.791 AC: 47722 AN: 60360

GnomAD4 genome AF: 0.756 AC: 114924 AN: 152098 Hom.: 44244 Cov.: 32 AF XY: 0.761 AC XY: 56575 AN XY: 74340

African (AFR) AF: 0.599 AC: 24846 AN: 41452

American (AMR) AF: 0.754 AC: 11520 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.829 AC: 2876 AN: 3470

East Asian (EAS) AF: 0.949 AC: 4907 AN: 5172

South Asian (SAS) AF: 0.839 AC: 4050 AN: 4826

European-Finnish (FIN) AF: 0.899 AC: 9525 AN: 10590

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.805 AC: 54726 AN: 67990

Other (OTH) AF: 0.740 AC: 1562 AN: 2112

Alfa AF: 0.762 Hom.: 33481

Bravo AF: 0.738

Asia WGS AF: 0.861 AC: 2994 AN: 3478

EpiCase AF: 0.793

EpiControl AF: 0.795

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Benign:6

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome Benign:2

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Mar 31, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.41
PhyloP100		-0.24
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2070093; hg19: chr2-215632256; COSMIC: COSV53617490;