chr17-61780253-CAACT-C

Variant names:

• chr17-61780253-CAACT-C
• rs766199221
• NM_032043.3:c.1935+4_1935+7delAGTT

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032043.3(BRIP1):​c.1935+4_1935+7delAGTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,694 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: BRIP1 NM_032043.3 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.58
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1935+4_1935+7delAGTT		splice_region intron	N/A	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.1935+4_1935+7delAGTT		splice_region intron	N/A	ENSP00000259008.2	Q9BX63-1
	BRIP1	ENST00000682453.1		c.1935+4_1935+7delAGTT		splice_region intron	N/A	ENSP00000506943.1	Q9BX63-1
	BRIP1	ENST00000683039.1		c.1935+4_1935+7delAGTT		splice_region intron	N/A	ENSP00000508303.1	Q9BX63-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000811 AC: 2 AN: 246476 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1450694 Hom.: 0 AF XY: 0.00000555 AC XY: 4 AN XY: 720984

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000302 AC: 1 AN: 33110

American (AMR) AF: 0.00 AC: 0 AN: 44162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 83148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52922

Middle Eastern (MID) AF: 0.000192 AC: 1 AN: 5200

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106754

Other (OTH) AF: 0.00 AC: 0 AN: 59944

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0249301), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Familial cancer of breast (1)
-	1	-	Familial cancer of breast;C1836860:Fanconi anemia complementation group J (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 7
DS_DL_spliceai		0.76		Position offset: 8

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

Other links and lift over

dbSNP: rs766199221; hg19: chr17-59857614;