chr2-214781242-A-G

Position:

• chr2-214781242-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000465.4(BARD1):​c.632T>C​(p.Leu211Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,595,312 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 2.33

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3695612).
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.632T>C	p.Leu211Ser	missense_variant	4/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.632T>C	p.Leu211Ser	missense_variant	4/11	1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000129 AC: 3 AN: 233342 Hom.: 0 AF XY: 0.00000793 AC XY: 1 AN XY: 126060

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: 0.00

Gnomad NFE exome AF: 0.0000277

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000187 AC: 27 AN: 1443146 Hom.: 0 Cov.: 34 AF XY: 0.0000139 AC XY: 10 AN XY: 717210

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 0.0000244

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 211 of the BARD1 protein (p.Leu211Ser). 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 breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 186956). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 08, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 27, 2023	The p.L211S variant (also known as c.632T>C), located in coding exon 4 of the BARD1 gene, results from a T to C substitution at nucleotide position 632. The leucine at codon 211 is replaced by serine, an amino acid with dissimilar properties. This variant has been reported in women with breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Young EL et al. J Med Genet, 2016 06;53:366-76). In another study, this alteration was observed in 0/3236 individuals with invasive epithelial ovarian cancer and in 1/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst., 2015 Nov;107). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2023	This missense variant replaces leucine with serine at codon 211 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419) and in an unaffected individual in an ovarian cancer risk case-control study (PMID: 26315354), and this variant also has been detected in a breast cancer case-control meta-analysis in 3/60466 cases and 6/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BARD1_000399). This variant has been identified in 4/264724 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

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2024

Not observed at significant frequency in large population cohorts (gnomAD); 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 of breast cancer, but also in healthy controls (PMID: 26315354, 25186627, 26976419, 26787654, 33471991); This variant is associated with the following publications: (PMID: 26976419, 25186627, 26315354, 26787654, 34326862, 33471991) -

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.Leu211Ser variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Tung_2016_26976419) as well as in 1 of 6862 chromosome (freq: 0.0001) of an unaffected control individual (Ramus_2015_26315354). The variant was also identified in the following databases: dbSNP (ID: rs762171436) as “With uncertain significance allele”, ClinVar and Clinvitae (3x as uncertain significance by Ambry Genetics, Invitae, GeneDx). The variant was not identified in Cosmic, MutDB or Zhejiang Colon Cancer Databases. The variant was identified in control databases in 1 of 30934 chromosomes at a frequency of 0.000032 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 8734 chromosomes (freq: 0.00011), while the variant was not observed in the Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. Although the p.Leu211 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Serine variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -

Malignant tumor of thyroid gland Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BARD1 p.Leu211Ser variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Tung_2016_26976419) as well as in 1 of 6862 chromosome (freq: 0.0001) of an unaffected control individual (Ramus_2015_26315354). The variant was also identified in the following databases: dbSNP (ID: rs762171436) as “With uncertain significance allele”, ClinVar and Clinvitae (3x as uncertain significance by Ambry Genetics, Invitae, GeneDx). The variant was not identified in Cosmic, MutDB or Zhejiang Colon Cancer Databases. The variant was identified in control databases in 1 of 30934 chromosomes at a frequency of 0.000032 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 8734 chromosomes (freq: 0.00011), while the variant was not observed in the Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. Although the p.Leu211 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Serine variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.60	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.73	D;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.23
MutPred		0.25		Gain of phosphorylation at L211 (P = 0.0119);.;
MVP		0.97
MPC		0.25
ClinPred		0.95	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.43

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: rs762171436; hg19: chr2-215645966;