rs1555576990

Variant names:

• chr17-43057132-CATGC-AATA
• rs1555576990
• NM_007294.4:c.5194-1_5197delGCATGinsTATT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PS3 PM2 PP5_Moderate

The NM_007294.4(BRCA1):​c.5194-1_5197delGCATGinsTATT​(p.His1732_Asp1733delinsIle???) variant causes a splice acceptor, missense, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000636019: An experimental study has shown that a different variant that has a similar effect on the splice acceptor (c.5194-1G>T, also known as IVS19-1G>T) either results in utilization of a cryptic splice site 13 nucleotides into exon 19 (called exon 20 in the paper), or in skipping of exon 19 completely (PMID:23239986).". Synonymous variant affecting the same amino acid position (i.e. H1732H) has been classified as Likely benign. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 splice_acceptor, missense, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.68
• Publications: 1 publications found

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 Gene-Disease associations (from GenCC):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.015021459 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.8, offset of 13, new splice context is: tctttcatattattttgaAGtca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000636019: An experimental study has shown that a different variant that has a similar effect on the splice acceptor (c.5194-1G>T, also known as IVS19-1G>T) either results in utilization of a cryptic splice site 13 nucleotides into exon 19 (called exon 20 in the paper), or in skipping of exon 19 completely (PMID: 23239986).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-43057132-CATGC-AATA is Pathogenic according to our data. Variant chr17-43057132-CATGC-AATA is described in ClinVar as Pathogenic. ClinVar VariationId is 462665.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.5194-1_5197delGCATGinsTATT	p.His1732_Asp1733delinsIle???	splice_acceptor missense splice_region intron	N/A	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5260-1_5263delGCATGinsTATT	p.His1754_Asp1755delinsIle???	splice_acceptor missense splice_region intron	N/A	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5260-1_5263delGCATGinsTATT	p.His1754_Asp1755delinsIle???	splice_acceptor missense splice_region intron	N/A	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5194-1_5197delGCATGinsTATT	p.His1732_Asp1733delinsIle???	splice_acceptor missense splice_region intron	N/A	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5257-1_5260delGCATGinsTATT	p.His1753_Asp1754delinsIle???	splice_acceptor missense splice_region intron	N/A	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5194-1_5197delGCATGinsTATT	p.His1732_Asp1733delinsIle???	splice_acceptor missense splice_region intron	N/A	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1555576990;

hg19: chr17-41209149;