17-43063945-TCAGC-TGCAGAATGAA

Variant names:

• chr17-43063946-CAGC-GCAGAATGAA
• rs397509224
• NM_007294.4:c.5077_5080delGCTGinsTTCATTCTGC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_001407581.1(BRCA1):​c.5143_5146delGCTGinsTTCATTCTGC​(p.Ala1715_Glu1716delinsPheIleLeuGln) 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 not provided (no stars). 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: not provided no classification provided O: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 6 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.

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_5080delGCTGinsTTCATTCTGC	p.Ala1693_Glu1694delinsPheIleLeuGln	missense conservative_inframe_insertion splice_region	N/A	NP_009225.1
	BRCA1	NM_001407581.1		c.5143_5146delGCTGinsTTCATTCTGC	p.Ala1715_Glu1716delinsPheIleLeuGln	missense conservative_inframe_insertion splice_region	N/A	NP_001394510.1
	BRCA1	NM_001407582.1		c.5143_5146delGCTGinsTTCATTCTGC	p.Ala1715_Glu1716delinsPheIleLeuGln	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_5080delGCTGinsTTCATTCTGC	p.Ala1693_Glu1694delinsPheIleLeuGln	missense conservative_inframe_insertion splice_region	N/A	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.5140_5143delGCTGinsTTCATTCTGC	p.Ala1714_Glu1715delinsPheIleLeuGln	missense conservative_inframe_insertion splice_region	N/A	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.5077_5080delGCTGinsTTCATTCTGC	p.Ala1693_Glu1694delinsPheIleLeuGln	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: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=1/199	disease causing

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;