rs45589637

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_032043.3(BRIP1):c.2220G>T(p.Gln740His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000575 in 1,613,890 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:12O:2

Conservation

PhyloP100: 0.274

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07559261).

BP6

Variant 17-61744469-C-A is Benign according to our data. Variant chr17-61744469-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133752.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=11, not_provided=2, Uncertain_significance=12}. Variant chr17-61744469-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.2220G>T	p.Gln740His	missense_variant	15/20	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.2220G>T	p.Gln740His	missense_variant	15/20	1	NM_032043.3	ENSP00000259008	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.000506

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000618

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000537

AC:

135

AN:

251286

Hom.:

AF XY:

0.000434

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000643

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000582

AC:

851

AN:

1461672

Hom.:

Cov.:

AF XY:

0.000556

AC XY:

404

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00143

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.000674

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000506

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000618

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000669

Hom.:

Bravo

AF:

0.000676

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:12Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BRIP1: BP4, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 20, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2016	Variant summary: The BRIP1 c.2220G>T (p.Gln740His) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 58/133810 control chromosomes at a frequency of 0.0004335, which is approximately 7 times the estimated maximal expected allele frequency of a pathogenic BRIP1 variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported in multiple cancer patients, however, a case-control study showed that this variant was not associated with breast cancer (OR=0.638, P=0.49, Haiman_2013). In addition, two patients carry the variant of interest and a pathogenic variant, homozygous MUTYH c.1187G>A/p.Gly396Asp and PALB2 c.3113G>A/W1038X, respectively (Yurgelun_2015, Kahn_2016), suggesting the variant of interest may be benign. On the other hand, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	This variant is associated with the following publications: (PMID: 28202063, 31159747, 25980754, 24728327, 26534844, 27547810, 26315354, 28528518, 26921362, 27978560, 28678401, 28767289, 31822495, 32039725, 31658756, 33115781) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 08, 2020	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 15, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 20, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 09, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 11, 2021	- -

Fanconi anemia complementation group J

Uncertain:3

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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 23, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 18, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP1. -

Familial cancer of breast

Uncertain:3

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jun 15, 2021	ACMG classification criteria: BS1 strong -

not specified

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 20, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

BRIP1-related disorder

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 05, 2019	The BRIP1 c.2220G>T (p.Gln740His) missense variant has been reported in at least four studies in which it is found in a heterozygous state in total of three individuals with Lynch syndrome, one of whom also carried a homozygous variant in the MUTYH gene (Bodian et al. 2014; Ramus et al. 2015; Yurgelun et al. 2015; Easton et al. 2016). The p.Gln740His variant was identified in a heterozygous state in six of 3431 controls and is reported at a frequency of 0.00140 in the Latino population of the Genome Aggregation Database. Based on the limited evidence, the p.Gln740His variant is classified as a variant of unknown significance but suspicious for pathogenicity for BRIP1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	May 17, 2023	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Likely benign and reported on 10-31-2019 by Lab 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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BRIP1 p.Gln740His variant was identified in 32 of 48608 proband chromosomes (frequency: 0.0007) from individuals or families with breast, ovarian cancer or Lynch syndrome and was present in 7 of 14818 control chromosomes (frequency: 0.0006) from healthy individuals (Easton 2016, Jalkh 2017, Li 2015, Penkert 2018, Ramus 2015, Tung 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs45589637) as "With other allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and nine other submitters; as likely benign by Integrated Genetics/Laboratory Corporation of America and GeneDx). The variant was identified in control databases in 144 of 277004 chromosomes at a frequency of 0.0005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 24024 chromosomes (freq: 0.00008), Other in 4 of 6460 chromosomes (freq: 0.0006), Latino in 48 of 34414 chromosomes (freq: 0.001), European in 82 of 126532 chromosomes (freq: 0.0007), Ashkenazi Jewish in 2 of 10148 chromosomes (freq: 0.0002), Finnish in 6 of 25780 chromosomes (freq: 0.0002); it was not observed in the East Asian, and South Asian populations. The p.Gln740 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Ovarian neoplasm

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 23, 2016

- -

Breast and/or ovarian cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 02, 2022

- -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.65

D;.

Eigen

Benign

-0.037

Eigen_PC

Benign

-0.081

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.83

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.076

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.0

M;M

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.2

N;.

REVEL

Uncertain

0.43

Sift

Benign

0.045

D;.

Sift4G

Uncertain

0.035

D;D

Polyphen

0.97

D;.

Vest4

0.41

MutPred

0.38

Gain of catalytic residue at D744 (P = 0.0907);Gain of catalytic residue at D744 (P = 0.0907);

MVP

0.89

MPC

0.42

ClinPred

0.041

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.58

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