2-214728728-C-T

Variant names:

• chr2-214728728-C-T
• rs142155101
• NM_000465.4:c.2282G>A

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.2282G>A​(p.Ser761Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,614,198 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:18
• Conservation: PhyloP100: 3.47

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=0.008288771).
• BP6: Variant 2-214728728-C-T is Benign according to our data. Variant chr2-214728728-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127735.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=8, Uncertain_significance=4}. Variant chr2-214728728-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00146 (223/152318) while in subpopulation NFE AF= 0.00123 (84/68022). AF 95% confidence interval is 0.00102. There are 1 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 223 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.2282G>A	p.Ser761Asn	missense_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.2282G>A	p.Ser761Asn	missense_variant	Exon 11 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152200 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00170 AC: 426 AN: 251230 Hom.: 1 AF XY: 0.00168 AC XY: 228 AN XY: 135768

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00943

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00108 AC: 1586 AN: 1461880 Hom.: 2 Cov.: 32 AF XY: 0.00106 AC XY: 770 AN XY: 727242

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00923

Gnomad4 NFE exome AF: 0.000845

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152318 Hom.: 1 Cov.: 32 AF XY: 0.00172 AC XY: 128 AN XY: 74494

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0113

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.000729

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00170 AC: 207

EpiCase AF: 0.000872

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:18

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:1 Benign:5

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. -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. -

Feb 24, 2023

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. 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]. -

Oct 26, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 09, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:4

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BARD1: BP4, BS1 -

Oct 28, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BARD1 c.2282G>A (p.Ser761Asn) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 222/129722 control chromosomes (3 homozygotes), predominantly observed in the European (Finnish) subpopulation in ExAC at a frequency of 0.0098366 (65/6608). This frequency is about 45 times the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. This variant has been reported in affected individuals with comparable MAF as in tested controls. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign, without evidence for independent evaluation. Functional studies showd that variant may lead to defective BARD1 function in growth suppression and apoptosis, however, this variant is shown not to affect the HDR activity. Taken all lines of evidence together, this variant is classified as likely benign until more information becomes available. -

Dec 21, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26787654, 26976419, 11807980, 28335968, 25980754, 18089818, 23056176, 17972171, 25288723, 17848578, 20077502, 16061562, 22006311, 26738429, 26350354, 9798686, 17550235, 9425226, 26898890, 26517685, 31159747) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:4

Oct 23, 2018

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. -

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 18, 2022

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Jul 11, 2017

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 08, 2020

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer Uncertain:1

Nov 20, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

May 23, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BARD1 p.Ser761Asn variant was identified in 2 of 1220 proband chromosomes (frequency: 0.002) from individuals or families with breast, ovarian, uterine and endometrial cancers, and was present in 2 of 966 control chromosomes (frequency: 0.002) from healthy individuals (De Brakeleer 2010, Gorringe 2008, Thai 1998). The variant was also identified in dbSNP (ID: rs142155101) as “With Uncertain significance allele”, ClinVar database (1x as benign by Invitae; 3x as likely benign by GeneDx, Ambry Genetics, Illumina; 1x as uncertain significance by CMGUMCL), Clinvitae database (classified as benign by Invitae; classified as likely benign and uncertain significance by ClinVar), MutDB, Zhejiang Colon Cancer Database (LOVD), databases. This variant was identified in the genome Aggregation Database (Genome Aggregation Consortium Feb 27, 2017) in 484 (3 homozygous) of 276958 chromosomes (freq. 0.002), in the following populations: Finnish in 247 of 25792 (2 homozygous) chromosomes (freq. 0.0095), Ashkenazi Jewish in 34 of 10146 chromosomes (freq. 0.0033), European in 189 of 126482 (1 homozygous) chromosomes (freq. 0.0015), other in 7 of 6460 chromosomes (freq. 0.001), Latino in 6 of 34406 chromosomes (freq. 0.00017), African in 1 of 24028 chromosomes (freq. 0.00004), increasing the likelihood this could be a low frequency benign variant. The variant p.Ser761Asn has been identified as cancer-associated missense mutation in breast and uterine cancers (Birrane 2007). This variant was also identified in a screen of 150 sporadic tumors and was not present in normal cells of the patients, indicating that they arose somatically during tumor development (Laufer 2007). The p.Ser761Asn variant was also identified as a somatic variant in endometrial cancer patient at age 8 with associated LOH (Thai 1998).The p.Ser761Asn variant is identified as putative disease associated allele (Sauer 2005).The p.Ser761 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 but we would lean towards a more benign role for this variant. It is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.;.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.00013
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;D;D;D;T;.
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.0083	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N;.;.;.;.;.
REVEL	Benign	0.059
Sift	Benign	0.091	T;.;.;.;.;.
Sift4G	Benign	0.16	T;T;T;T;T;T
Polyphen		0.0070	B;.;.;.;.;.
Vest4		0.097
MVP		0.86
MPC		0.077
ClinPred		0.029	T
GERP RS		3.8
Varity_R		0.21
gMVP		0.66

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: rs142155101; hg19: chr2-215593452; COSMIC: COSV104530907; COSMIC: COSV104530907;