NM_000465.4:c.69_70delGCinsTCCGGGAACGAGCCTCGTTCCGCGT

Variant names:

• chr2-214809500-GC-ACGCGGAACGAGGCTCGTTCCCGGA
• rs876659040
• NM_000465.4:c.69_70delGCinsTCCGGGAACGAGCCTCGTTCCGCGT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000465.4(BARD1):​c.69_70delGCinsTCCGGGAACGAGCCTCGTTCCGCGT​(p.Ala25GlyfsTer41) variant causes a frameshift, missense 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. AP23VS) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: BARD1 NM_000465.4 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.990
• Publications: 3 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]

SNHG31 (HGNC:54196): (small nucleolar RNA host gene 31)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 515 pathogenic variants in the truncated region.
• PP5: Variant 2-214809500-GC-ACGCGGAACGAGGCTCGTTCCCGGA is Pathogenic according to our data. Variant chr2-214809500-GC-ACGCGGAACGAGGCTCGTTCCCGGA is described in ClinVar as Pathogenic. ClinVar VariationId is 231232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000465.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.69_70delGCinsTCCGGGAACGAGCCTCGTTCCGCGT	p.Ala25GlyfsTer41	frameshift missense	Exon 1 of 11	NP_000456.2
	BARD1	NM_001282543.2		c.69_70delGCinsTCCGGGAACGAGCCTCGTTCCGCGT	p.Ala25GlyfsTer40	frameshift missense	Exon 1 of 10	NP_001269472.1
	BARD1	NM_001282545.2		c.69_70delGCinsTCCGGGAACGAGCCTCGTTCCGCGT	p.Ala25GlyfsTer41	frameshift missense	Exon 1 of 7	NP_001269474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.69_70delGCinsTCCGGGAACGAGCCTCGTTCCGCGT	p.Ala25GlyfsTer41	frameshift missense	Exon 1 of 11	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.69_70delGCinsTCCGGGAACGAGCCTCGTTCCGCGT	p.Ala25GlyfsTer40	frameshift missense	Exon 1 of 10	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.69_70delGCinsTCCGGGAACGAGCCTCGTTCCGCGT	p.Ala25GlyfsTer41	frameshift missense	Exon 1 of 11	ENSP00000484976.2

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Familial cancer of breast (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.99

Splicing

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

Other links and lift over

dbSNP: rs876659040; hg19: chr2-215674224;