chr2-214792428-C-G

Variant names:

• chr2-214792428-C-G
• rs199780731
• NM_000465.4:c.233G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_000465.4(BARD1):​c.233G>C​(p.Cys78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,455,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C78R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.96
• 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 35 uncertain in NM_000465.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.33368832).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.233G>C	p.Cys78Ser	missense_variant	Exon 3 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.233G>C	p.Cys78Ser	missense_variant	Exon 3 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1455026 Hom.: 0 Cov.: 32 AF XY: 0.0000180 AC XY: 13 AN XY: 723516

African (AFR) AF: 0.00 AC: 0 AN: 33116

American (AMR) AF: 0.00 AC: 0 AN: 43852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.00 AC: 0 AN: 84648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1109216

Other (OTH) AF: 0.00 AC: 0 AN: 60040

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:2

Jun 19, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 78 of the BARD1 protein (p.Cys78Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 421438). 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. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 29367421). 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:2

Jun 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C78S variant (also known as c.233G>C), located in coding exon 3 of the BARD1 gene, results from a G to C substitution at nucleotide position 233. The cysteine at codon 78 is replaced by serine, an amino acid with dissimilar properties. This variant is located in the BARD1 RING domain but does not coordinate zinc binding. In one study, p.C78S demonstrated ability to ubiquitylate H2A on nucleosomes similar to wild type BARD1, a function necessary for homologous recombination (Stewart MD et al. Proc. Natl. Acad. Sci. U.S.A., 2018 02;115:1316-1321). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jun 23, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 26, 2019

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.233G>C (p.Cys78Ser) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 243944 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.233G>C in individuals affected with Breast Cancer has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Stewart_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Jun 14, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BARD1 c.233G>C at the cDNA level, p.Cys78Ser (C78S) at the protein level, and results in the change of a Cysteine to a Serine (TGC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Cys78Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Cys78Ser occurs at a position that is conserved in mammals and is located in the RING-type Zinc finger domain as well as a region known to interact with BRCA1 (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BARD1 Cys78Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.0058	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.16	T;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.40	N;.;.;N
PhyloP100		2.0
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	N;.;.;.
REVEL	Uncertain	0.38
Sift	Benign	0.64	T;.;.;.
Sift4G	Benign	0.56	T;D;T;T
Polyphen		0.30	B;.;.;.
Vest4		0.77
MutPred		0.56		Gain of glycosylation at C78 (P = 0.0341);Gain of glycosylation at C78 (P = 0.0341);.;Gain of glycosylation at C78 (P = 0.0341);
MVP		0.96
MPC		0.11
ClinPred		0.50	D
GERP RS		4.5
Varity_R		0.24
gMVP		0.49
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199780731; hg19: chr2-215657152;