2-214730497-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_000465.4(BARD1):c.1915T>C(p.Cys639Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C639G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 7.68

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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• BS2: High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.1915T>C	p.Cys639Arg	missense_variant	10/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.1915T>C	p.Cys639Arg	missense_variant	10/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152170 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251322 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1461640 Hom.: 0 Cov.: 30 AF XY: 0.0000454 AC XY: 33 AN XY: 727114

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 639 of the BARD1 protein (p.Cys639Arg). This variant is present in population databases (rs587781376, gnomAD 0.009%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26534844, 30613976, 31036035, 31159747, 31512090, 35264596). ClinVar contains an entry for this variant (Variation ID: 140927). 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 disruptive. 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. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 15, 2016	Variant summary: The c.1915T>C (p.Cys639Arg) in BARD1 gene is a missense change that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant falls into the BRCT domain, and mutations in this domain have been shown to be associated with cancer. The variant is present in the control population dataset of ExAC at an overall frequency 0.000017 (2/121244 chrs tested). This frequency does not exceed the estimated maximum allele frequency for a pathogenic allele in this gene (0.0002). The variant was identified in at least 1 HBOC BRCA1&2-negative family, with no information on segregation and co-occurrence provided by the authors (Li, 2016). The variant of interest has been reported as VUS by reputable database/clinical laboratory. Additional clinical, segregation and population data needed to classify this variant with confidence. Taking together, the variant was classified as VUS. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2021	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast and/ovarian cancer (Li 2016, Scarpitta 2019, Weber-Lassalle 2019); This variant is associated with the following publications: (PMID: 17550235, 31036035, 31512090, 26534844, 31159747, 27535533) -

Hereditary cancer-predisposing syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 13, 2023	The p.C639R variant (also known as c.1915T>C), located in coding exon 10 of the BARD1 gene, results from a T to C substitution at nucleotide position 1915. The cysteine at codon 639 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been identified in numerous disease cohorts as well as unaffected control groups across studies (Li J et al. J. Med. Genet., 2016 Jan;53:34-42; Scarpitta R et al. Breast Cancer Res Treat, 2019 Dec;178:557-564; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Weber-Lassalle N et al. Breast Cancer Res, 2019 04;21:55; Dorling et al. N Engl J Med. 2021 02;384:428-439; Rizzolo P et al. Int J Cancer, 2019 Jul;145:390-400; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 01, 2023	This missense variant replaces cysteine with arginine at codon 639 of the BARD1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 26534844, 31036035, 31159747, 31512090, 36980780). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 6/60466 cases and 4/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BARD1_000127). This variant has been identified in 7/251322 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.;T;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;T;D;D;D;.;.
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-8.7	D;.;.;.;.;.;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;.;.;.;.;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.82
MutPred		0.74		Gain of MoRF binding (P = 0.0081);.;.;.;.;.;.;
MVP		0.93
MPC		0.57
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.95

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: rs587781376; hg19: chr2-215595221;