rs578022079

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_032043.3(BRIP1):c.2593C>T(p.Arg865Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:14

Conservation

PhyloP100: 3.48

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 Uncertain_significance. Variant got 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3 link	c.2593C>T	p.Arg865Trp	missense_variant	Exon 19 of 20	ENST00000259008.7	NP_114432.2	Q9BX63-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 link	c.2593C>T	p.Arg865Trp	missense_variant	Exon 19 of 20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152116

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250326

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74438

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Nov 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R865W variant (also known as c.2593C>T), located in coding exon 18 of the BRIP1 gene, results from a C to T substitution at nucleotide position 2593. The arginine at codon 865 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). This alteration has also been identified in 1/976 alleles from a cohort of Dutch melanomaprone families (Potjer TP et al. Int. J. Cancer, 2019 05;144:2453-2464). In one study, the p.R865W alteration was detected in 6/101,759 breast cancer cases and 2/15,587 ovarian cancer cases (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867), and was reported in 5/60,466 breast cancer cases and in 2/53,461 controls in another study (Dorling et al. N Engl J Med 2021 02;384:428-439). This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). In an inter-strand cross link damage survival assay, the p.R865W alteration was found to be functionally abnormal (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Apr 21, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 08, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with tryptophan at codon 865 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study has reported the mutant protein to be defective for repair of interstrand crosslink damage in a BRIP1-/- HeLa cell growth rescue assay (PMID: 31822495). This variant has been reported in an individual with breast cancer (PMID: 29368626) and in an individual with melanoma (PMID: 30414346), as well as in a few individuals unaffected with cancer (PMID: 29368626, 29641532). In one study, this variant was observed in 6/101,759 individuals with breast cancer, in 2/15,587 individuals with ovarian cancer, and in 2/9,884 FLOSSIES individuals (women over age 70 lacking personal history of cancer; PMID: 31822495). In an international breast cancer case-control meta-analysis, this variant was detected in 5/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 8/281722 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. -

not specified

Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRIP1 c.2593C>T (p.Arg865Trp) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250326 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2593C>T has been reported in the literature in individuals affected with breast or ovarian cancer (e.g. Weber-Lassalle_2018, Moyer_2020, de Oliveira_2022). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 5/60466 cases, but was also found in 2/53461 controls (Dorling_2021 through LOVD). The variant has also been found in 2/7,325 women of European American ancestry who were over 70 years of age, and never had cancer (FLOSSIES database). In addition, the variant was reported in one individual with melanoma from a melanoma-affected family, but the variant did not co-segregate with disease (Potjer_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had a reduced half-life in vitro compared to the wild-type protein and was unable to rescue a BRIP1 null phenotype in an inter-strand cross link damage survival assay (Moyer_2020). The following publications have been ascertained in the context of this evaluation (PMID: 30414346, 29368626, 31822495, 33471991, 35534704). ClinVar contains an entry for this variant (Variation ID: 230320). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:2

Dec 07, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect: demonstrates inability to rescue growth in cell viability assays (PMID: 31822495); This variant is associated with the following publications: (PMID: 30414346, 29368626, 29641532, 33471991, 35534704, 31822495, 35264596, Ma2019[article]) -

Oct 02, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRIP1 c.2593C>T (p.Arg865Trp) variant has been reported in individuals with breast/ovarian cancer (PMIDs: 29368626 (2018), 29641532 (2018), 31822495 (2019), 33471991 (2021), 35534704 (2022), 35264596 (2022), see also LOVD (http://databases.lovd.nl/shared)) and melanoma (PMID: 30414346 (2019)). In addition, this variant has been identified in reportedly healthy individuals (PMID: 3471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). A functional study indicated this variant causes reduced protein stability and impaired DNA interstrand cross-link repair in a cell survival assay (PMID: 31822495 (2019)). The frequency of this variant in the general population, 0.000047 (6/128716 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Familial cancer of breast

Uncertain:2

Feb 19, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Uncertain:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 865 of the BRIP1 protein (p.Arg865Trp). This variant is present in population databases (rs578022079, gnomAD 0.005%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 29368626, 31822495, 35534704). ClinVar contains an entry for this variant (Variation ID: 230320). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRIP1 protein function. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 31822495). 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. -

BRIP1-related disorder

Uncertain:1

Jun 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRIP1 c.2593C>T variant is predicted to result in the amino acid substitution p.Arg865Trp. This variant has been reported in individuals with melanoma, breast cancer, and ovarian cancer (Table 2, Moyer et al. 2019. PubMed ID: 31822495; Table 4, Potjer et al. 2019. PubMed ID: 30414346; Table S3, Weber-Lassalle et al. 2018. PubMed ID; 29368626). It has also been reported in control individuals from several cancer cohort studies (Table S3, Weber-Lassalle et al. 2018. PubMed ID; 29368626; Table S3, Prichard et al. 2018. PubMed ID: 29641532). In vitro experimental studies suggest that this variant may impair protein activity (Table 12, Moyer et al. 2019. PubMed ID: 31822495). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/230320/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Ovarian neoplasm;C1836860:Fanconi anemia complementation group J

Uncertain:1

May 17, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group J

Uncertain:1

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Feb 18, 2025

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ACMG SVI adaptation criteria we chose these criteria: PS3 (supporting pathogenic): Moyer, 2020 (PMID: 31822495): Classified as null allele; impaired protein's ability to repair inter-strand cross link damage in transfected cells (CRISPR-Cas9 gene editing to create isogenic HeLa cell lines lacking BRIP1 protein and/or expressing candidate missense) , PP3 (medium pathogenic): REVEL = 0.804 (thus [0.773, 0.932) as per Pejaver (2022, PMID: 36413997)) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.7

H;H

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.0

D;.

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.84

MVP

1.0

MPC

0.70

ClinPred

1.0

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.89

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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