chr2-214781318-T-C

Variant names:

• chr2-214781318-T-C
• rs16852741
• NM_000465.4:c.556A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1 PP3_Moderate BP6 BS1 BS2_Supporting

The NM_000465.4(BARD1):​c.556A>G​(p.Ser186Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,612,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:3
• Conservation: PhyloP100: 1.55

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity BARD1_HUMAN
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-214781318-T-C is Benign according to our data. Variant chr2-214781318-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 230396.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=9}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000329 (5/152202) while in subpopulation EAS AF= 0.000962 (5/5198). AF 95% confidence interval is 0.000379. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.556A>G	p.Ser186Gly	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.556A>G	p.Ser186Gly	missense_variant	Exon 4 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

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

GnomAD3 exomes AF: 0.0000480 AC: 12 AN: 250122 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000599

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1460616 Hom.: 0 Cov.: 34 AF XY: 0.0000385 AC XY: 28 AN XY: 726378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00161

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000962

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:3

Feb 07, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 186 of the BARD1 protein (p.Ser186Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of BARD1-related conditions (PMID: 25186627, 30982232, 31666926, 32068069, 33309985, 34754157). ClinVar contains an entry for this variant (Variation ID: 230396). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Dec 06, 2022

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, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 13, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2022

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.556A>G (p.Ser186Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250122 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BARD1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.00025). However, the variant was found in the East Asian population at a frequency that is 2.4 fold above the maximum expected allele frequency for a pathogenic variant, suggesting the variant is a benign polymorphism in the East Asian population. c.556A>G has been reported in the literature in individuals affected with breast, colorectal and biliary tract cancer as well as in patients with PJS, without strong evidence for causality (Tung_2015, Wang_2019, Terashima_2019, Kwong_2020, Fujita_2020, Gu_2021). 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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Seven submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

not provided Uncertain:2

Nov 11, 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; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in individuals with breast and pancreatic cancer, but also in unaffected controls (Tung et al., 2015; Mizukami et al., 2020); This variant is associated with the following publications: (PMID: 19139070, 23056176, 25186627, 32566746, 32980694) -

Sep 16, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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.Ser186Gly variant was not identified in the literature nor was it identified in the Cosmic, or MutDB databases. The variant was identified in dbSNP (ID: rs16852741) as “With Uncertain significance allele”, ClinVar (as uncertain significance by Ambry Genetics, GeneDx, Color Genomics, Invitae, and Laboratory Corporation of America), Clinvitae (3x as in ClinVar), and Zhejiang Colon Cancer Database (1x). The variant was identified in control databases in 12 of 244950 chromosomes at a frequency of 0.000049 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 1 of 5462 chromosomes (freq: 0.000183), East Asian in 11 of 17222 chromosomes (freq: 0.000639), while the variant was not observed in the African, Latino, European (Non-Finnish), Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Ser186Gly 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 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In addition, the variant was identified with a co-occurring pathogenic PALB2 variant (p.Arg414X), increasing the likelihood that the p.Ser186Gly variant does not have clinical significance. 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 Uncertain:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Ovarian cancer Benign:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

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	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.066	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.15
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.38	B;.
Vest4		0.21
MutPred		0.059		Loss of phosphorylation at S186 (P = 0.0085);.;
MVP		0.90
MPC		0.10
ClinPred		0.071	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.93		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs16852741; hg19: chr2-215646042; COSMIC: COSV53613848;