Genetic Variant BRIP1:p.Pro47Thr (chr17-61859860-GGG-CGT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_032043.3(BRIP1):c.139_141delCCCinsACG (p.Pro47Thr) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.46). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P47A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 4736); p.P47H: Uncertain_significance (ClinVar VariationId 3228087, 1 star); p.P47= (synonymous): Benign/Likely_benign (ClinVar VariationId 2032308, 2 stars); p.P47R: Uncertain_significance (ClinVar VariationId 3482466, 2 stars); p.P47S: Uncertain_significance (ClinVar VariationId 4082934, 2 stars); p.P47T: Uncertain_significance (ClinVar VariationId 182340, 2 stars)

Frequency

Genomes: not found (cov: 32)

Consequence

BRIP1
NM_032043.3 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.46

Publications

0 publications found

Variant links:

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: Orphanet, Illumina
Fanconi anemia complementation group J
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
colorectal adenoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRIP1 links:

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new If you want to explore the variant's impact on the transcript NM_032043.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 points.

PM2

Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000287 by highest known P/LP ClinVar AF 0.000287) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_032043.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	NM_032043.3	MANE Select	c.139_141delCCCinsACG	p.Pro47Thr	missense	N/A	NP_114432.2	Q9BX63-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRIP1	ENST00000259008.7	TSL:1 MANE Select	c.139_141delCCCinsACG	p.Pro47Thr	missense	N/A	ENSP00000259008.2	Q9BX63-1
BRIP1	ENST00000682453.1		c.139_141delCCCinsACG	p.Pro47Thr	missense	N/A	ENSP00000506943.1	Q9BX63-1
BRIP1	ENST00000683039.1		c.139_141delCCCinsACG	p.Pro47Thr	missense	N/A	ENSP00000508303.1	Q9BX63-1

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.5

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over