Variant 17-61683582-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032043.3(BRIP1):c.3464G>A(p.Gly1155Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,612,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9O:2

Conservation

PhyloP100: -0.0350

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042932898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.3464G>A	p.Gly1155Glu	missense_variant	20/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.3464G>A	p.Gly1155Glu	missense_variant	20/20	1	NM_032043.3	ENSP00000259008	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250092

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135292

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1460340

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

726526

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 06, 2023	This missense variant replaces glycine with glutamic acid at codon 1155 of the BRIP1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 16280053, 17033622, 26921362, 26976419). In a large breast cancer case-control study, this variant was observed in 1/60466 cases and 1/53461 unaffected controls (OR=0.884, 95%CI 0.055 to 14.136) (PMID: 33471991). This variant has been identified in 4/250092 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 25, 2022	The p.G1155E variant (also known as c.3464G>A), located in coding exon 19 of the BRIP1 gene, results from a G to A substitution at nucleotide position 3464. The glycine at codon 1155 is replaced by glutamic acid, an amino acid with similar properties. This variant has previously been reported in a BRCA1/2-negative female affected with breast cancer; however, the variant did not segregate with disease in the family (Lewis AG et al. Breast Cancer Res. 2005; 7(6):R1005-16). This alteration has also been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 09, 2021	- -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1155 of the BRIP1 protein (p.Gly1155Glu). This variant is present in population databases (rs45603843, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 16280053, 17033622, 26976419, 27997549). ClinVar contains an entry for this variant (Variation ID: 128189). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 27, 2021	- -

not provided

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or ovarian cancer in the published literature (Lewis 2005, Seal 2006, Easton 2016, Maxwell 2016, Tung 2016); This variant is associated with the following publications: (PMID: 16280053, 26976419, 17033622, 26921362, 27997549, 27153395) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 22, 2022

DNA sequence analysis of the BRIP1 gene demonstrated a sequence change, c.3464G>A, in exon 20 that results in an amino acid change, p.Gly1155Glu. This sequence change has been reported in individual(s) affected with personal history of breast cancer (PMID: 17033622, 26921362, 26976419) and/or family history of breast and ovarian cancer (PMID: 16280053). This sequence change has been described in the gnomAD database in the European (non-Finnish) subpopulation in four individuals that corresponds to a population frequency of 0.0035% (dbSNP rs45603843). The p.Gly1155Glu change affects a poorly conserved amino acid residue located in a domain of the BRIP1 protein that is not known to be functional. The p.Gly1155Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly1155Glu change remains unknown at this time. -

Ovarian neoplasm;C1836860:Fanconi anemia complementation group J

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jun 01, 2017

- -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Mar 02, 2023

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Fanconi anemia complementation group J

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 05-26-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.15

DANN

Benign

0.33

DEOGEN2

Benign

0.081

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0086

LIST_S2

Benign

0.53

M_CAP

Benign

0.020

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

MutationTaster

Benign

1.0

PrimateAI

Benign

0.21

PROVEAN

Benign

0.060

REVEL

Benign

0.063

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.037

MutPred

0.14

Gain of solvent accessibility (P = 0.012);

MVP

0.57

MPC

0.21

ClinPred

0.0069

GERP RS

-2.5

Varity_R

0.032

gMVP

0.14

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over