17-61859862-G-C

Variant names:

• chr17-61859862-G-C
• rs28903098
• NM_032043.3:c.139C>G
• BRIP1 p.Pro47Ala

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACMG Germline Pathogenicity v2019). PS3PP3BP6

The NM_032043.3(BRIP1):c.139C>G (p.Pro47Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000355 (AC=573) in the gnomAD database across 1,613,850 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.000425. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 8.46). Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). ClinVar reports functional evidence for this variant: "SCV001167103: The helicase activity of the P47A mutant protein is defective, as described by Cantor, and BRIP1 is an interacting BRCA1 protein, we consider this mutation to be clinically important and treatment target in our patient. PMID:11301010, PMID:18473727, https://doi.org/10.2217/fon.10.191". Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): 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) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:24 B:9
• Conservation: PhyloP100: 8.46
• Publications: 47 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: 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

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Uncertain_significance. The variant received 4 points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV001167103: The helicase activity of the P47A mutant protein is defective, as described by Cantor, and BRIP1 is an interacting BRCA1 protein, we consider this mutation to be clinically important and treatment target in our patient. PMID:11301010, PMID:18473727, https://doi.org/10.2217/fon.10.191
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
• BP6: ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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.139C>G	p.Pro47Ala	missense	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.139C>G	p.Pro47Ala	missense	Exon 3 of 20	ENSP00000259008.2	Q9BX63-1
	BRIP1	ENST00000682453.1		c.139C>G	p.Pro47Ala	missense	Exon 4 of 21	ENSP00000506943.1	Q9BX63-1
	BRIP1	ENST00000683039.1		c.139C>G	p.Pro47Ala	missense	Exon 4 of 21	ENSP00000508303.1	Q9BX63-1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000247 AC: 62 AN: 251410 AF XY: 0.000265

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000368 AC: 538 AN: 1461574 Hom.: 1 Cov.: 30 AF XY: 0.000396 AC XY: 288 AN XY: 727094

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86240

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53396

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.000459 AC: 510 AN: 1111810

Other (OTH) AF: 0.000232 AC: 14 AN: 60376

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74462

African (AFR) AF: 0.000120 AC: 5 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000375 Hom.: 0

Bravo AF: 0.000223

EpiCase AF: 0.000382

EpiControl AF: 0.00107

Local populations

Turkish Variome AF: 0.00104 AC: 7 AN: 6724 Hom.: 0

ABraOM SABE-WGS-1171 AF: 0.000427 AC: 1 AN: 2342 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	9	1	not provided (10)
-	1	4	Hereditary cancer-predisposing syndrome (5)
-	3	-	Familial cancer of breast (3)
-	3	-	Fanconi anemia complementation group J (3)
-	1	2	not specified (3)
1	1	-	Breast cancer, early-onset (2)
-	1	1	Familial cancer of breast;C1836860:Fanconi anemia complementation group J (2)
1	1	-	Malignant tumor of breast (2)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	BRIP1-related disorder (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	1	-	Monogenic short stature (1)
-	1	-	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Benign	0.95
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.013	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.70
Sift	Benign	0.055	T
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
gMVP		0.84
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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.

Other links and lift over

dbSNP: rs28903098;

hg19: chr17-59937223;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar