rs16852741

chr2-214781318-T-Cchr2-214781318-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.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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S186I) has been classified as Uncertain significance.

• 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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06616315).
• 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, Uncertain_significance=9, Benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000452 (66/1460616) while in subpopulation EAS AF= 0.00161 (64/39682). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4_exome. There are 28 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.556A>G	p.Ser186Gly	missense_variant	4/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.556A>G	p.Ser186Gly	missense_variant	4/11	1	NM_000465.4	P2

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	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 (Invitae). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 13, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 06, 2022	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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2022	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 16, 2020	- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 01, 2022

- -

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;.
MutationTaster	Benign	1.0	N;N
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;