2-214727991-ATGTACAGAATAAAAATATGTACCATGAGCCTAGTGTTGATTTTTACCACACACACAAAAAAACCAATGTTAATGATTAAATCACAATTTCCTGATGATATACAAGATAAAAAACAGGGATGAAAGTGTAGAAACACACAACAAAGTAAATTATTAAGAAAAGAAATGAACACAATATAGGATAAAGACAATTGCAGATAGGAGAATTTAACACCTATGGTGGCACATTTAGACCAAATACTCTTTTTTCAATAAAGCCAAAATAAATTGTTTGATAATATTCTGTTTACTAAAAAAAAAAAAAAAAAAAAGGCAAGTTTTTTCACTGGTGGCAGGTATGGAGAATATTAAAAGACTCAAACAGTAATGATACCACTTGTCTATTTAACCAAGATTCTGGTGTCCTCATTAATCTTTGATACCCAATAATCTGAATAGAAAGACATGATAAATCAAAAACATGCCAATTTTAAAAAGAAAAACCTTTAAAAGCAATCCCAGCTTCTAAATGGTAAACATAACATGAATTCCTAATCTGGCATTAGACTTTTTTTTTTTTTTTGATTCAAAGACAAATATGAATGACTCTACCTATTTGTAAAAATGTGAACATTAAAAACAGTACAATGACTGGGCTCTCACAAACCGTGCAAATTCAATTTGAAATGTTCATCTGGTATAATATTCAGC-A

Variant names:

• chr2-214727991-ATGTACAGAATAAAAATATGTACCATGAGCCTAGTGTTGATTTTTACCACACACACAAAAAAACCAATGTTAATGATTAAATCACAATTTCCTGATGATATACAAGATAAAAAACAGGGATGAAAGTGTAGAAACACACAACAAAGTAAATTATTAAGAAAAGAAATGAACACAATATAGGATAAAGACAATTGCAGATAGGAGAATTTAACACCTATGGTGGCACATTTAGACCAAATACTCTTTTTTCAATAAAGCCAAAATAAATTGTTTGATAATATTCTGTTTACTAAAAAAAAAAAAAAAAAAAAGGCAAGTTTTTTCACTGGTGGCAGGTATGGAGAATATTAAAAGACTCAAACAGTAATGATACCACTTGTCTATTTAACCAAGATTCTGGTGTCCTCATTAATCTTTGATACCCAATAATCTGAATAGAAAGACATGATAAATCAAAAACATGCCAATTTTAAAAAGAAAAACCTTTAAAAGCAATCCCAGCTTCTAAATGGTAAACATAACATGAATTCCTAATCTGGCATTAGACTTTTTTTTTTTTTTTGATTCAAAGACAAATATGAATGACTCTACCTATTTGTAAAAATGTGAACATTAAAAACAGTACAATGACTGGGCTCTCACAAACCGTGCAAATTCAATTTGAAATGTTCATCTGGTATAATATTCAGC-A
• rs1692152873
• NM_000465.4:c.2330_*684del

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_000465.4(BARD1):​c.2330_*684del​(p.Ser777fs) variant causes a frameshift, stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 frameshift, stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• Publications: 0 publications found

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]

BARD1 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.2330_*684del	p.Ser777fs	frameshift_variant, stop_lost	Exon 11 of 11	ENST00000260947.9	NP_000456.2
BARD1	NM_000465.4	c.2330_*684del		3_prime_UTR_variant	Exon 11 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.2330_*684del	p.Ser777fs	frameshift_variant, stop_lost	Exon 11 of 11	1	NM_000465.4	ENSP00000260947.4
BARD1	ENST00000260947.9	c.2330_*684del		3_prime_UTR_variant	Exon 11 of 11	1	NM_000465.4	ENSP00000260947.4

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

May 06, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 variant has not been reported in the literature in individuals with BARD1-related conditions. This variant is not present in population databases (ExAC no frequency). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3

Splicing

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

Other links and lift over

dbSNP: rs1692152873; hg19: chr2-215592715;