2-214767531-C-T

Variant names:

• chr2-214767531-C-T
• rs2070094
• NM_000465.4:c.1519G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000465.4(BARD1):​c.1519G>A​(p.Val507Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,612,252 control chromosomes in the GnomAD database, including 109,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V507L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.37 (10608 hom., cov: 32)
  • Exomes 𝑓: 0.37 (99049 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -5.22
• Publications: 86 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3202429E-4).
• BP6: Variant 2-214767531-C-T is Benign according to our data. Variant chr2-214767531-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 140757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1519G>A	p.Val507Met	missense_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.1519G>A	p.Val507Met	missense_variant	Exon 6 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56406 AN: 151950 Hom.: 10590 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.379

GnomAD2 exomes AF: 0.374 AC: 93956 AN: 251276 AF XY: 0.376

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.416

Gnomad EAS exome AF: 0.366

Gnomad FIN exome AF: 0.468

Gnomad NFE exome AF: 0.371

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.366 AC: 535041 AN: 1460184 Hom.: 99049 Cov.: 42 AF XY: 0.368 AC XY: 267556 AN XY: 726492

African (AFR) AF: 0.367 AC: 12263 AN: 33408

American (AMR) AF: 0.298 AC: 13315 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 10613 AN: 26124

East Asian (EAS) AF: 0.358 AC: 14201 AN: 39686

South Asian (SAS) AF: 0.407 AC: 35057 AN: 86218

European-Finnish (FIN) AF: 0.472 AC: 25187 AN: 53396

Middle Eastern (MID) AF: 0.385 AC: 2220 AN: 5766

European-Non Finnish (NFE) AF: 0.360 AC: 400164 AN: 1110540

Other (OTH) AF: 0.365 AC: 22021 AN: 60336

GnomAD4 genome AF: 0.371 AC: 56462 AN: 152068 Hom.: 10608 Cov.: 32 AF XY: 0.376 AC XY: 27971 AN XY: 74330

African (AFR) AF: 0.371 AC: 15396 AN: 41480

American (AMR) AF: 0.319 AC: 4870 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1447 AN: 3468

East Asian (EAS) AF: 0.372 AC: 1921 AN: 5166

South Asian (SAS) AF: 0.412 AC: 1987 AN: 4824

European-Finnish (FIN) AF: 0.467 AC: 4939 AN: 10568

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24734 AN: 67966

Other (OTH) AF: 0.379 AC: 799 AN: 2108

Alfa AF: 0.361 Hom.: 24188

Bravo AF: 0.354

ESP6500AA AF: 0.290 AC: 1278

ESP6500EA AF: 0.276 AC: 2372

ExAC AF: 0.378 AC: 45922

Asia WGS AF: 0.378 AC: 1313 AN: 3478

EpiCase AF: 0.357

EpiControl AF: 0.354

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Benign:4

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

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 has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25785002, 27153395, 26350354, 14550946, 19412175, 9425226, 23222812) -

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. -

Nov 04, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0080
DANN	Benign	0.66
DEOGEN2	Benign	0.064	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.50	T;T
MetaRNN	Benign	0.00013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		-5.2
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.3	N;.
REVEL	Benign	0.11
Sift	Benign	0.27	T;.
Sift4G	Uncertain	0.039	D;D
Polyphen		0.058	B;.
Vest4		0.026
MPC		0.077
ClinPred		0.024	T
GERP RS		-11
Varity_R		0.11
gMVP		0.12
Mutation Taster		=97/3	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: rs2070094; hg19: chr2-215632255; COSMIC: COSV53610001;