rs587782675

chr2-214809475-C-Achr2-214809475-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000465.4(BARD1):c.95G>T(p.Gly32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000994 in 1,609,936 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G32S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 1.15

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.95G>T	p.Gly32Val	missense_variant	1/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.95G>T	p.Gly32Val	missense_variant	1/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1457692 Hom.: 0 Cov.: 76 AF XY: 0.0000138 AC XY: 10 AN XY: 725100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74382

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 27, 2023	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. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 26350354). 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. ClinVar contains an entry for this variant (Variation ID: 142728). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 32 of the BARD1 protein (p.Gly32Val). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 24, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 24, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 09, 2021	The p.G32V variant (also known as c.95G>T), located in coding exon 1 of the BARD1 gene, results from a G to T substitution at nucleotide position 95. The glycine at codon 32 is replaced by valine, an amino acid with dissimilar properties. Functional analyses demonstrates that this alteration retains 87% homology-directed repair function compared to wild-type (Lee C et al. Hum. Mutat. 2015 Dec;36(12):1205-14). This variant has also been identified in 19/12503 unselected Japanese colorectal cancer patients and in 29/23705 controls. (Fujita M et al. Clin Gastroenterol Hepatol, 2020 Dec;:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Jun 23, 2019	- -

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

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 20, 2023

Variant summary: BARD1 c.95G>T (p.Gly32Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 236358 control chromosomes (gnomAD). However, the variant was reported at a frequency of 0.00067 (2.4 fold above the maximum pathogenic allele frequency) in a Japanese control population (jMorp) and in controls from a case-control study (Fujita_2022). To our knowledge, there are no reports of c.95G>T in individuals affected with Breast Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.6014_6017delATAG, p.Asp2005ValfsX34; internal sample), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal homology-directed repair activity (Lee_2015). The following publications have been ascertained in the context of this evaluation (PMID: 26350354, 30925164, 33309985). Five clinical diagnostic laboratories have submitted clinical-significance assessments (all uncertain significance) for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.;.;T;.;.
Eigen	Benign	0.091
Eigen_PC	Benign	-0.0090
FATHMM_MKL	Benign	0.054	N
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;.
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.8	L;.;L;.;.;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N;.;.;.;.;.;N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.98	D;.;.;.;.;.;.
Vest4		0.40
MutPred		0.24		Loss of catalytic residue at G32 (P = 0.0286);Loss of catalytic residue at G32 (P = 0.0286);Loss of catalytic residue at G32 (P = 0.0286);Loss of catalytic residue at G32 (P = 0.0286);Loss of catalytic residue at G32 (P = 0.0286);Loss of catalytic residue at G32 (P = 0.0286);Loss of catalytic residue at G32 (P = 0.0286);
MVP		0.98
MPC		0.48
ClinPred		0.92	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.32

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: rs587782675; hg19: chr2-215674199;