rs397509224

Variant names:

• chr17-43063946-CAGC-GCAGAATCAA
• rs397509224
• NM_007294.4:c.5077_5080delGCTGinsTTGATTCTGC

Your query was ambiguous. Multiple possible variants found:

• chr17-43063945-TCAGC-TGCAGAATCAA
• chr17-43063945-TCAGC-TGCAGAATGAA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM4 PP5_Moderate

The NM_001407581.1(BRCA1):​c.5143_5146delGCTGinsTTGATTCTGC​(p.Ala1715_Glu1716delinsLeuIleLeuGln) variant causes a missense, conservative inframe insertion, splice region 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A1715A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_001407581.1 missense, conservative_inframe_insertion, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.32
• 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):

• breast-ovarian cancer, familial, susceptibility to, 1

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

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

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

• PM1: In a hotspot region, there are 30 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 68 uncertain in NM_001407581.1
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001407581.1.
• PP5: Variant 17-43063946-CAGC-GCAGAATCAA is Pathogenic according to our data. Variant chr17-43063946-CAGC-GCAGAATCAA is described in ClinVar as Pathogenic. ClinVar VariationId is 267576.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407581.1. 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
	BRCA1	NM_007294.4	MANE Select	c.5077_5080delGCTGinsTTGATTCTGC	p.Ala1693_Glu1694delinsLeuIleLeuGln	missense conservative_inframe_insertion splice_region	N/A	NP_009225.1
	BRCA1	NM_001407581.1		c.5143_5146delGCTGinsTTGATTCTGC	p.Ala1715_Glu1716delinsLeuIleLeuGln	missense conservative_inframe_insertion splice_region	N/A	NP_001394510.1
	BRCA1	NM_001407582.1		c.5143_5146delGCTGinsTTGATTCTGC	p.Ala1715_Glu1716delinsLeuIleLeuGln	missense conservative_inframe_insertion splice_region	N/A	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5077_5080delGCTGinsTTGATTCTGC	p.Ala1693_Glu1694delinsLeuIleLeuGln	missense conservative_inframe_insertion splice_region	N/A	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.5140_5143delGCTGinsTTGATTCTGC	p.Ala1714_Glu1715delinsLeuIleLeuGln	missense conservative_inframe_insertion splice_region	N/A	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.5077_5080delGCTGinsTTGATTCTGC	p.Ala1693_Glu1694delinsLeuIleLeuGln	missense conservative_inframe_insertion splice_region	N/A	ENSP00000419274.2

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3

Splicing

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

Other links and lift over

dbSNP: rs397509224; hg19: chr17-41215963;