2-214727991-ATGTACAGAATAAAAATATGTACCATGAGCCTAGTGTTGATTTTTACCACACACACAAAAAAACCAATGTTAATGATTAAATCACAATTTCCTGATGATATACAAGATAAAAAACAGGGATGAAAGTGTAGAAACACACAACAAAGTAAATTATTAAGAAAAGAAATGAACACAATATAGGATAAAGACAATTGCAGATAGGAGAATTTAACACCTATGGTGGCACATTTAGACCAAATACTCTTTTTTCAATAAAGCCAAAATAAATTGTTTGATAATATTCTGTTTACTAAAAAAAAAAAAAAAAAAAAGGCAAGTTTTTTCACTGGTGGCAGGTATGGAGAATATTAAAAGACTCAAACAGTAATGATACCACTTGTCTATTTAACCAAGATTCTGGTGTCCTCATTAATCTTTGATACCCAATAATCTGAATAGAAAGACATGATAAATCAAAAACATGCCAATTTTAAAAAGAAAAACCTTTAAAAGCAATCCCAGCTTCTAAATGGTAAACATAACATGAATTCCTAATCTGGCATTAGACTTTTTTTTTTTTTTTGATTCAAAGACAAATATGAATGACTCTACCTATTTGTAAAAATGTGAACATTAAAAACAGTACAATGACTGGGCTCTCACAAACCGTGCAAATTCAATTTGAAATGTTCATCTGGTATAATATTCAGC-A

Position:

• chr2-214727991-ATGTACAGAATAAAAATATGTACCATGAGCCTAGTGTTGATTTTTACCACACACACAAAAAAACCAATGTTAATGATTAAATCACAATTTCCTGATGATATACAAGATAAAAAACAGGGATGAAAGTGTAGAAACACACAACAAAGTAAATTATTAAGAAAAGAAATGAACACAATATAGGATAAAGACAATTGCAGATAGGAGAATTTAACACCTATGGTGGCACATTTAGACCAAATACTCTTTTTTCAATAAAGCCAAAATAAATTGTTTGATAATATTCTGTTTACTAAAAAAAAAAAAAAAAAAAAGGCAAGTTTTTTCACTGGTGGCAGGTATGGAGAATATTAAAAGACTCAAACAGTAATGATACCACTTGTCTATTTAACCAAGATTCTGGTGTCCTCATTAATCTTTGATACCCAATAATCTGAATAGAAAGACATGATAAATCAAAAACATGCCAATTTTAAAAAGAAAAACCTTTAAAAGCAATCCCAGCTTCTAAATGGTAAACATAACATGAATTCCTAATCTGGCATTAGACTTTTTTTTTTTTTTTGATTCAAAGACAAATATGAATGACTCTACCTATTTGTAAAAATGTGAACATTAAAAACAGTACAATGACTGGGCTCTCACAAACCGTGCAAATTCAATTTGAAATGTTCATCTGGTATAATATTCAGC-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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 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
BARD1	NM_000465.4	c.2330_*684del		stop_lost, 3_prime_UTR_variant	11/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.2330_*684del		stop_lost, 3_prime_UTR_variant	11/11	1	NM_000465.4	P2

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

Submissions by phenotype

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 06, 2019

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 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1692152873; hg19: chr2-215592715;