rs138904906

Variant names:

• chr2-214781110-T-C
• rs138904906
• NM_000465.4:c.764A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-214781110-T-C
• chr2-214781110-T-G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000465.4(BARD1):​c.764A>G​(p.Asn255Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000228 in 1,582,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N255T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2
• Conservation: PhyloP100: 0.904
• Publications: 4 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07121819).
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000154 (22/1429728) while in subpopulation AFR AF = 0.000628 (20/31828). AF 95% confidence interval is 0.000416. There are 0 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000465.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.764A>G	p.Asn255Ser	missense	Exon 4 of 11	NP_000456.2
	BARD1	NM_001282543.2		c.707A>G	p.Asn236Ser	missense	Exon 3 of 10	NP_001269472.1
	BARD1	NR_104212.2		n.729A>G		non_coding_transcript_exon	Exon 3 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.764A>G	p.Asn255Ser	missense	Exon 4 of 11	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.707A>G	p.Asn236Ser	missense	Exon 3 of 10	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.764A>G	p.Asn255Ser	missense	Exon 4 of 11	ENSP00000484976.2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000271 AC: 6 AN: 221662 AF XY: 0.0000168

Gnomad AFR exome AF: 0.000383

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000154 AC: 22 AN: 1429728 Hom.: 0 Cov.: 34 AF XY: 0.00000988 AC XY: 7 AN XY: 708562

African (AFR) AF: 0.000628 AC: 20 AN: 31828

American (AMR) AF: 0.0000257 AC: 1 AN: 38906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24168

East Asian (EAS) AF: 0.00 AC: 0 AN: 39444

South Asian (SAS) AF: 0.00 AC: 0 AN: 79756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5572

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098808

Other (OTH) AF: 0.0000170 AC: 1 AN: 58876

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74480

African (AFR) AF: 0.000265 AC: 11 AN: 41568

American (AMR) AF: 0.000196 AC: 3 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000389 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:5

Feb 24, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 255 of the BARD1 protein (p.Asn255Ser). This variant is present in population databases (rs138904906, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 32039725, 32866190, 32885271). ClinVar contains an entry for this variant (Variation ID: 245891). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

Oct 22, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 17, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:2

Nov 11, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31871109, 23056176, 32039725, 32885271, 32832836, 32866190)

Sep 28, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Apr 12, 2024

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.

Jul 15, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces asparagine with serine at codon 255 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been identified in individuals affected with breast cancer (PMID: 31871109, 32039725, 32866190, 32885271). This variant has been identified in 8/253060 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

not specified Uncertain:1

Jul 13, 2023

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.764A>G (p.Asn255Ser) results in a 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 2.7e-05 in 221662 control chromosomes, predominantly at a frequency of 0.00038 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.764A>G has been reported in the literature in individuals affected with breast cancer without strong evidence of causality (Adedokun_2020, Bishop_2020, Carvalho_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23056176, 32039725, 31871109, 32866190). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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.Asn255Ser variant was not identified in the literature. The variant was identified in dbSNP (rs138904906) as “with uncertain significance allele”, ClinVar (interpreted as "uncertain significance" by Invitae and 5 others). The variant was identified in control databases in 8 of 247,792 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 8 of 23,516 chromosomes (freq: 0.0003), but not in the “Other”, Latino, European, Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The p.Asn255 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; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.90
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.24
Sift	Benign	0.26	T
Sift4G	Benign	0.15	T
Polyphen		0.96	D
Vest4		0.17
MVP		0.90
MPC		0.071
ClinPred		0.080	T
GERP RS		3.4
Varity_R		0.093
gMVP		0.11
Mutation Taster		=92/8	polymorphism

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: rs138904906; hg19: chr2-215645834;