rs145009419

Variant names:

• chr2-214781206-T-C
• rs145009419
• NM_000465.4:c.668A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-214781206-T-C
• chr2-214781206-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000465.4(BARD1):​c.668A>G​(p.Glu223Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,591,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13 B:6
• Conservation: PhyloP100: 0.190

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04667273).
• BP6: Variant 2-214781206-T-C is Benign according to our data. Variant chr2-214781206-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127743.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=11}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000249 (38/152324) while in subpopulation NFE AF= 0.000485 (33/68030). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.668A>G	p.Glu223Gly	missense_variant	Exon 4 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.668A>G	p.Glu223Gly	missense_variant	Exon 4 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000485

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000161 AC: 37 AN: 229148 Hom.: 0 AF XY: 0.000169 AC XY: 21 AN XY: 123902

Gnomad AFR exome AF: 0.0000640

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000951

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000185 AC: 266 AN: 1439510 Hom.: 0 Cov.: 34 AF XY: 0.000171 AC XY: 122 AN XY: 715320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.000227

Gnomad4 OTH exome AF: 0.000118

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74490

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:6 Benign:1

Apr 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BARD1 c.668A>G; p.Glu223Gly variant (rs145009419; ClinVar Variation ID: 127743) is reported in the literature in individuals affected with breast cancer (Bhai 2021, Caminsky 2016, Lerner-Ellis 2021, Tung 2016), endometrial cancer (Ring 2016), bone and urological tumors (Jahn 2022) and an individual suspected of Lynch syndrome (Yurgelun 2015). This variant is found in the non-Finnish European population with an allele frequency of 0.03% (41/122772 alleles) in the Genome Aggregation Database (v2.1.1). Functional analyses of the variant protein show homology directed repair activity comparable to the wildtype protein (Adamovich 2019). Computational analyses predict that this variant is neutral (REVEL: 0.085). However, based on the available information, the clinical significance of this variant is uncertain at this time. References: Adamovich AI et al. Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity. PLoS Genet. 2019 Mar 29;15(3):e1008049. PMID: 30925164. Bhai P et al. Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. Front Genet. 2021 Jul 13;12:698595. PMID: 34326862. Caminsky NG et al. Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations. Hum Mutat. 2016 Jul;37(7):640-52. PMID: 26898890. Jahn A et al. Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers. Ann Oncol. 2022 Nov;33(11):1186-1199. PMID: 35988656. Lerner-Ellis J et al. Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. J Cancer Res Clin Oncol. 2021 Mar;147(3):871-879. PMID: 32885271. Ring KL et al. Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. Mod Pathol. 2016 Nov;29(11):1381-1389. PMID: 27443514. Tung N et al. Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer. J Clin Oncol. 2016 May 1;34(13):1460-8. PMID: 26976419. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. PMID: 25980754. -

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 24, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 223 of the BARD1 protein (p.Glu223Gly). This variant is present in population databases (rs145009419, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer or clinical features of Lynch syndrome (PMID: 25186627, 25980754, 26976419). ClinVar contains an entry for this variant (Variation ID: 127743). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 30925164). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 22, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:3

Aug 30, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the BARD1 gene demonstrated a sequence change, c.668A>G, in exon 4 that results in an amino acid change, p.Glu223Gly. This sequence change has been described in the gnomAD database with frequency of 0.033% in the non-Finnish European subpopulation (dbSNP rs145009419). The p.Glu223Gly change affects a moderately conserved amino acid residue located in a domain of the BARD1 protein that is not known to be functional. The p.Glu223Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in individuals who underwent germline genetic testing based on a personal history of breast cancer or a Lynch syndrome-associated cancer (PMID: 26976419, 25980754). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu223Gly change remains unknown at this time. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BARD1 c.668A>G (p.Glu223Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 229148 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BARD1 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00016 vs 0.00025), allowing no conclusion about variant significance. The variant has also been found in 5/7325 European American women over the age of 70 with no personal history of cancer (FLOSSIES database). c.668A>G has been reported in the literature in individuals with suspected Lynch syndrome, affected with breast cancer and endometrial cancer without strong evidence of causality (Tung_2015, Yurgelun_2015, Ring_2016), as well as in individuals with family histories suggesting Hereditary Breast And Ovarian Cancer (Caminsky_2016) and breast cancer (Dorling_2021). Co-occurrences with other pathogenic variant(s) have been reported (CHEK2 c.1100del , p.Thr367Metfs*15). Functional assays using homology directed repair of two non-functional GFP coding sequences showed the variant had similar HDR activity as wild-type BARD1, showing no damaging effect of this variant (Adamovich_2019). The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 23056176, 25186627, 26898890, 27443514, 30925164, 33471991). ClinVar contains an entry for this variant (Variation ID: 127743). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1 Benign:2

Jan 28, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate homology-directed repair activity similar to wild-type (Adamovich 2019); This variant is associated with the following publications: (PMID: 23056176, 27742771, 25980754, 26976419, 26898890, 27443514, 28873162, 25186627, 30925164, 27535533) -

Aug 14, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BARD1: BP4, BS1:Supporting, BS3:Supporting -

Hereditary cancer-predisposing syndrome Benign:3

Sep 19, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2020

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 27, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Breast and/or ovarian cancer Uncertain:1

Apr 14, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BARD1-related disorder Uncertain:1

Apr 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BARD1 c.668A>G variant is predicted to result in the amino acid substitution p.Glu223Gly. This variant has been identified in an individual suspected of Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant was also identified in individuals with breast and/or ovarian cancer (Table A2, Tung et al. 2016. PubMed ID: 26976419; Table S9, Caminsky et al. 2016. PubMed ID: 26898890), endometrial cancer (Table S2, Ring et al. 2016. PubMed ID: 27443514), as well as in an individual with advanced cancer (type unspecified) (eTable, Mandelker et al. 2017. PubMed ID: 28873162). In the aforementioned studies, no evidence was provided to determine the pathogenicity of this variant. This variant has been observed with a minor allele frequency of up to 0.033% in a large population database, and is reported in ClinVar with interpretations ranging from likely benign to variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127743/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BARD1 p.Glu223Gly variant was identified in 2 of 3496 proband chromosomes (frequency 0.00057) from American individuals with Lynch syndrome-associated cancer and/or polyps and breast cancer (Yurgelun_2015_25980754, Tung_2016_26976419). The variant was also identified in dbSNP (ID: rs145009419) as “With Uncertain significance allele”, ClinVar and Clinvitae (4x classified as uncertain significance by GeneDx, Ambry Genetics, Invitae, and Fulgent Genetics), and the Zhejiang Colon Cancer Database (1 entry, pathogenicity unknown). The variant was not identified in the COSMIC or MutDB databases. The variant was identified in control databases in 41 of 255258 chromosomes at a frequency of 0.00016 increasing the likelihood this could be a low frequency variant in certain populations (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 23436 chromosomes (freq: 0.000043), European Non-Finnish in 38 of 120160 chromosomes (freq: 0.00032), European Finnish in 2 of 25186 chromosomes (freq: 0.00008); it was not observed in the “Other”, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Glu223Gly residue is conserved in mammals but not in more distantly related organisms, however, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein, but this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.2	N;.
REVEL	Benign	0.085
Sift	Benign	0.16	T;.
Sift4G	Benign	0.17	T;T
Polyphen		0.0	B;.
Vest4		0.099
MVP		0.70
MPC		0.088
ClinPred		0.025	T
GERP RS		0.64
Varity_R		0.064
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs145009419; hg19: chr2-215645930;