2-214809568-A-G

Variant names:

• chr2-214809568-A-G
• rs1553628504
• NM_000465.4:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000465.4(BARD1):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: BARD1 NM_000465.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.27
• Publications: 1 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 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 16 pathogenic variants. Next in-frame start position is after 26 codons. Genomic position: 214809494. Lost 0.033 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.2T>C	p.Met1?	start_lost	Exon 1 of 11	NP_000456.2
	BARD1	NM_001282543.2		c.2T>C	p.Met1?	start_lost	Exon 1 of 10	NP_001269472.1
	BARD1	NM_001282545.2		c.2T>C	p.Met1?	start_lost	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.2T>C	p.Met1?	start_lost	Exon 1 of 11	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 11	ENSP00000484976.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 73

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jun 11, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Uncertain:1

Nov 22, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the BARD1 mRNA. However, another in-frame methionine that is highly conserved in mammals is located 25 codons downstream (p.Met26) and could potentially rescue the loss of initiator codon. In summary, this variant is a novel initiatior codon change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Experimental studies have not been reported for this initiation codon variant and it is currently unknown if translation is rescued by either an in-frame or out-of-frame methionine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a BARD1-related disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.060	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.33	T
PhyloP100		3.3
PROVEAN	Benign	-0.52	N
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.90	P
Vest4		0.76
MutPred		0.98		Gain of phosphorylation at M1 (P = 0.002)
MVP		0.94
ClinPred		0.99	D
GERP RS		4.0
PromoterAI		0.077	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.95
gMVP		0.47
Mutation Taster		=41/159	disease causing

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

Other links and lift over

dbSNP: rs1553628504; hg19: chr2-215674292;