chr2-214727991-ATGTACAGAATAAAAATATGTACCATGAGCCTAGTGTTGATTTTTACCACACACACAAAAAAACCAATGTTAATGATTAAATCACAATTTCCTGATGATATACAAGATAAAAAACAGGGATGAAAGTGTAGAAACACACAACAAAGTAAATTATTAAGAAAAGAAATGAACACAATATAGGATAAAGACAATTGCAGATAGGAGAATTTAACACCTATGGTGGCACATTTAGACCAAATACTCTTTTTTCAATAAAGCCAAAATAAATTGTTTGATAATATTCTGTTTACTAAAAAAAAAAAAAAAAAAAAGGCAAGTTTTTTCACTGGTGGCAGGTATGGAGAATATTAAAAGACTCAAACAGTAATGATACCACTTGTCTATTTAACCAAGATTCTGGTGTCCTCATTAATCTTTGATACCCAATAATCTGAATAGAAAGACATGATAAATCAAAAACATGCCAATTTTAAAAAGAAAAACCTTTAAAAGCAATCCCAGCTTCTAAATGGTAAACATAACATGAATTCCTAATCTGGCATTAGACTTTTTTTTTTTTTTTGATTCAAAGACAAATATGAATGACTCTACCTATTTGTAAAAATGTGAACATTAAAAACAGTACAATGACTGGGCTCTCACAAACCGTGCAAATTCAATTTGAAATGTTCATCTGGTATAATATTCAGC-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_000465.4(BARD1):​c.2330_*684del variant causes a stop lost, 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S777S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

BARD1
NM_000465.4 stop_lost, 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BARD1NM_000465.4 linkuse as main transcriptc.2330_*684del stop_lost, 3_prime_UTR_variant 11/11 ENST00000260947.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BARD1ENST00000260947.9 linkuse as main transcriptc.2330_*684del stop_lost, 3_prime_UTR_variant 11/111 NM_000465.4 P2Q99728-1

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMay 06, 2019In 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 and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This sequence change results in a frameshift in the BARD1 gene (p.Ser777Ilefs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last amino acid of the BARD1 protein and extend the protein by an additional 2 amino acids. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BARD1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1692152873; hg19: chr2-215592715; API