Variant rs587780230 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032043.3(BRIP1):c.1467T>G(p.Ile489Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000523 in 1,605,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 0.238

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:

BRIP1 (HGNC:):

BRIP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22274595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.1467T>G	p.Ile489Met	missense_variant	10/20	ENST00000259008.7	NP_114432.2	Q9BX63-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.1467T>G	p.Ile489Met	missense_variant	10/20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

241248

Hom.:

AF XY:

0.00

AC XY:

AN XY:

130100

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:

0.0000278

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000571

AC:

AN:

1453202

Hom.:

Cov.:

AF XY:

0.0000512

AC XY:

AN XY:

722306

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.0000740

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

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	Ambry Genetics	Dec 08, 2022	The p.I489M variant (also known as c.1467T>G) is located in coding exon 9 of the BRIP1 gene. This alteration results from a T to G substitution at nucleotide position 1467. The isoleucine at codon 489 is replaced by methionine, an amino acid with highly similar properties. Based on protein sequence alignment, this amino acid position is not well 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	Oct 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2023	This missense variant replaces isoleucine with methionine at codon 489 of the BRIP1 protein. Computational prediction 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 tubo-ovarian cancer or breast cancer (PMID: 33471991, 35263119). This variant has been identified in 3/241248 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. -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 09, 2021	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 23, 2022

Variant summary: BRIP1 c.1467T>G (p.Ile489Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 241248 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1467T>G has been reported in the literature in at-least one individual affected with Ovarian Cancer (example: Delahunty_2022). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 489 of the BRIP1 protein (p.Ile489Met). This variant is present in population databases (rs587780230, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 128161). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRIP1 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33471991, 35263119) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

0.061

Eigen_PC

Benign

0.013

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.2

N;.

REVEL

Uncertain

0.31

Sift

Benign

0.045

D;.

Sift4G

Benign

0.13

T;T

Polyphen

0.97

D;.

Vest4

0.28

MVP

0.80

MPC

0.49

ClinPred

0.48

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.29

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