rs370359540

chr2-214792408-C-Achr2-214792408-C-Gchr2-214792408-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000465.4(BARD1):c.253G>T(p.Val85Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,610,076 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V85A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00052 (8 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.47

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01702416).
• BP6: Variant 2-214792408-C-A is Benign according to our data. Variant chr2-214792408-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 142450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000347 (52/149710) while in subpopulation SAS AF= 0.00993 (47/4732). AF 95% confidence interval is 0.00768. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.253G>T	p.Val85Leu	missense_variant	3/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.253G>T	p.Val85Leu	missense_variant	3/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.000341 AC: 51 AN: 149606 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000668

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00970

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000999 AC: 250 AN: 250290 Hom.: 3 AF XY: 0.00125 AC XY: 169 AN XY: 135284

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00800

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000518 AC: 757 AN: 1460366 Hom.: 8 Cov.: 32 AF XY: 0.000727 AC XY: 528 AN XY: 726388

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00797

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.000347 AC: 52 AN: 149710 Hom.: 0 Cov.: 30 AF XY: 0.000549 AC XY: 40 AN XY: 72916

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000667

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000198

Gnomad4 SAS AF: 0.00993

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000443

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000229 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00106 AC: 129

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2018	This variant is associated with the following publications: (PMID: 27153395, 30925164, 20077502, 26738429, 28202063) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	BARD1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 29, 2019	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 13, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 03, 2017	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 09, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 11, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 14, 2021	- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BARD1 p.Val85Leu variant was identified in 2 of 482 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer and was present in 2 of 450 control chromosomes (frequency: 0.004) from healthy individuals (De Brakeleer 2010, Jalkh 2017). The variant was also identified in the following databases: dbSNP (ID: rs370359540) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx; classified as benign by Invitae), Clinvitae (classified as uncertain significance by ClinVar), and the Zhejiang Colon Cancer Database. The variant was not identified in Cosmic, or MutDB databases. The variant was identified in control databases in 256 (3 homozygous) of 275536 chromosomes at a frequency of 0.001 in the following populations: South Asian in 247 of 30554 chromosomes (freq. 0.008), European Non-Finnish in 5 of 126084 chromosomes (freq. 0.00004), African in 2 of 23898 chromosomes (freq. 0.0001), East Asian in 1 of 18764 chromosomes (freq. 0.0001), Other in 1 of 6380 chromosomes (freq. 0.0001), increasing the likelihood this could be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Val85 residue is 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 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant was identified with a co-occurring pathogenic BRCA1 variant (c.C4327T p.R1443X), increasing the likelihood that the p.Val85Leu variant does not have clinical significance (Jalkh 2017). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T;T;D;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.017	T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.49	N;.;.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.18	T;.;.;.
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.78	P;.;.;.
Vest4		0.61
MutPred		0.30		Gain of stability (P = 0.0886);Gain of stability (P = 0.0886);.;Gain of stability (P = 0.0886);
MVP		0.87
MPC		0.26
ClinPred		0.059	T
GERP RS		5.3
Varity_R		0.32
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs370359540; hg19: chr2-215657132; COSMIC: COSV53615969; COSMIC: COSV53615969;