rs1555618396

Variant names:

• chr17-61859822-G-GCAGAACAAAGTAAGGCTAAGCTTTTTCCACTTCCTGTGGGACTCTCCAACAAACAATGTTGCTTGCTGTTTAATCCTCTGAGAATCTATGAA
• rs1555618396
• NM_032043.3:c.94-7_178dupTTCATAGATTCTCAGAGGATTAAACAGCAAGCAACATTGTTTGTTGGAGAGTCCCACAGGAAGTGGAAAAAGCTTAGCCTTACTTTGTTCTG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_032043.3(BRIP1):​c.94-7_178dupTTCATAGATTCTCAGAGGATTAAACAGCAAGCAACATTGTTTGTTGGAGAGTCCCACAGGAAGTGGAAAAAGCTTAGCCTTACTTTGTTCTG​(p.Ala60ValfsTer8) variant causes a frameshift, stop gained change. 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 (★). Synonymous variant affecting the same amino acid position (i.e. A60A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRIP1 NM_032043.3 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.98
• Publications: 1 publications found

Genes affected

BRIP1 (HGNC:20473): (BRCA1 interacting helicase 1) The protein encoded by this gene is a member of the RecQ DEAH helicase family and interacts with the BRCT repeats of breast cancer, type 1 (BRCA1). The bound complex is important in the normal double-strand break repair function of breast cancer, type 1 (BRCA1). This gene may be a target of germline cancer-inducing mutations. [provided by RefSeq, Jul 2008]

BRIP1 Gene-Disease associations (from GenCC):

• familial ovarian cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• Fanconi anemia complementation group J

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, ClinGen
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-61859822-G-GCAGAACAAAGTAAGGCTAAGCTTTTTCCACTTCCTGTGGGACTCTCCAACAAACAATGTTGCTTGCTGTTTAATCCTCTGAGAATCTATGAA is Pathogenic according to our data. Variant chr17-61859822-G-GCAGAACAAAGTAAGGCTAAGCTTTTTCCACTTCCTGTGGGACTCTCCAACAAACAATGTTGCTTGCTGTTTAATCCTCTGAGAATCTATGAA is described in ClinVar as Pathogenic. ClinVar VariationId is 407793.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032043.3. 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
	BRIP1	NM_032043.3	MANE Select	c.94-7_178dupTTCATAGATTCTCAGAGGATTAAACAGCAAGCAACATTGTTTGTTGGAGAGTCCCACAGGAAGTGGAAAAAGCTTAGCCTTACTTTGTTCTG	p.Ala60ValfsTer8	frameshift stop_gained	Exon 3 of 20	NP_114432.2	Q9BX63-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	ENST00000259008.7	TSL:1 MANE Select	c.178_179insTTCATAGATTCTCAGAGGATTAAACAGCAAGCAACATTGTTTGTTGGAGAGTCCCACAGGAAGTGGAAAAAGCTTAGCCTTACTTTGTTCTG	p.Ala60ValfsTer8	frameshift stop_gained	Exon 3 of 20	ENSP00000259008.2	Q9BX63-1
	BRIP1	ENST00000682453.1		c.178_179insTTCATAGATTCTCAGAGGATTAAACAGCAAGCAACATTGTTTGTTGGAGAGTCCCACAGGAAGTGGAAAAAGCTTAGCCTTACTTTGTTCTG	p.Ala60ValfsTer8	frameshift stop_gained	Exon 4 of 21	ENSP00000506943.1	Q9BX63-1
	BRIP1	ENST00000683039.1		c.178_179insTTCATAGATTCTCAGAGGATTAAACAGCAAGCAACATTGTTTGTTGGAGAGTCCCACAGGAAGTGGAAAAAGCTTAGCCTTACTTTGTTCTG	p.Ala60ValfsTer8	frameshift stop_gained	Exon 4 of 21	ENSP00000508303.1	Q9BX63-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Familial cancer of breast;C1836860:Fanconi anemia complementation group J (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555618396; hg19: chr17-59937183;