NM_032043.3:c.2233G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_032043.3(BRIP1):c.2233G>A(p.Ala745Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000415 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A745V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:18B:1

Conservation

PhyloP100: 5.69

Publications

16 publications found

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 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, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary breast carcinoma
Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
colorectal adenoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3 link	c.2233G>A	p.Ala745Thr	missense_variant	Exon 15 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.2233G>A	p.Ala745Thr	missense_variant	Exon 15 of 20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000864

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

GnomAD2 exomes

AF:

0.0000836

AC:

AN:

251244

AF XY:

0.0000957

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461620

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000995

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1111876

Other (OTH)

AF:

0.0000331

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41406

American (AMR)

AF:

0.000131

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000165

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:18Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:6

Nov 10, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Sep 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A745T variant (also known as c.2233G>A), located in coding exon 14 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2233. The alanine at codon 745 is replaced by threonine, an amino acid with similar properties. This variant has been reported in multiple individuals considered high-risk for breast and /or ovarian cancer (Catucci I et al. Fam. Cancer. 2012 Sep;11:483-91; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This alteration has also been identified in individuals diagnosed with breast, ovarian and/or pancreatic cancer (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:; Wang J et al. Cancer Med, 2019 05;8:2074-2084; Moyer CL et al. Cancer Res. 2020 Feb;80:857-867; Yin L et al. JAMA Netw Open, 2022 Feb;5:e2148721). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Oct 14, 2015

Vantari Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2018

GeneKor MSA

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with threonine at codon 745 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. A functional study reported this variant to be wild-type in protein stability and sensitivity and cell cycle progression assays to mitomycin C and cisplatin treatment (PMID: 31822495). This variant has been reported in individuals affected with personal or family history of breast and/or ovarian cancer (PMID: 22692731, 26315354, 26921362, 31822495, 33471991), as well as in unaffected control individuals (PMID: 29368626, 31822495, 33471991). This variant has also been identified in 20/246024 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. -

Jun 04, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:3

Apr 24, 2025

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.2233G>A (p.Ala745Thr) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251244 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BRIP1 causing Fanconi Anemia Complementation Group J (8.4e-05 vs 0.0004), allowing no conclusion about variant significance. c.2233G>A has been reported in the literature in individuals affected with BRIP1-associated cancers (Ramus_2015, Maxwell_2016, Easton_2016, Catucci_2012, Weber-Lassalle_2018, Moyer_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Complementation Group J. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5946delT, p.Ser1982fsX22), providing supporting evidence for a benign role. In functional studies, the variant did not significantly affect protein function (Moyer_2020). The following publications have been ascertained in the context of this evaluation (PMID: 25846551, 22692731, 26921362, 27153395, 26709662, 26315354, 29368626, 31822495). ClinVar contains an entry for this variant (Variation ID: 128169). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Apr 11, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast

Uncertain:3

May 03, 2023

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRIP1 c.2233G>A (p.Ala745Thr) missense change has a maximum founder subpopulation frequency of 0.096% and a maximum non-founder subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, but published functional studies demonstrate no damaging effect (PMID: 31822495). The variant has been reported in individuals with breast and/or ovarian cancer (PMID: 22692731, 26315354, 26921362, 27153395, 31822495). This variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Mar 02, 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. -

Mar 05, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:2Benign:1

Apr 24, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with a personal or family history of breast, ovarian, and other cancers, but also in unaffected controls (PMID: 31822495, 29368626, 26921362, 26315354, 22692731, 30982232, 33471991, 35171259, 38136308); Published functional studies demonstrate protein stability, lack of mitomycin C and cisplatin sensitivity similar to wild-type, and conflicting impact on protein expression (PMID: 31822495, 38177925); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22895193, 26709662, 22692731, 25846551, 26315354, 25957691, 26832770, 27153395, 26921362, 28420421, 28873162, 29368626, 31159747, 31822495, 33471991, 30982232, 36907870, 35171259, 38177925, 38136308) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 18, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:2

Mar 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 745 of the BRIP1 protein (p.Ala745Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 22692731, 26315354, 30982232, 31822495). ClinVar contains an entry for this variant (Variation ID: 128169). 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) indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect 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. -

Ovarian cancer;C1836860:Fanconi anemia complementation group J

Uncertain:1

Sep 06, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

BRIP1-related disorder

Uncertain:1

Apr 08, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BRIP1 c.2233G>A variant is predicted to result in the amino acid substitution p.Ala745Thr. This variant has been reported in individuals with hereditary breast cancer and/or ovarian cancer/pancreatic cancer (Catucci et al. 2012. PubMed ID: 22692731; Ramus et al. 2015. PubMed ID: 26315354, Table S4; Easton et al. 2016. PubMed ID: 26921362, Table S1; Maxwell et al. 2016. PubMed ID: 27153395, Tables S4 and S5; Weber-Lassalle et al. 2018. PubMed ID: 29368626, Table S3; Moyer et al. 2019. PubMed ID: 31822495; Yin et al. 2022. PubMed ID: 35171259, Table e4). It has also been reported in an individual undergoing hereditary cancer testing and interpreted as uncertain significance (Tsaousis et al. 2019. PubMed ID: 31159747, Table S5). However, this variant has also been reported in control individuals (Weber-Lassalle et al. 2018. PubMed ID: 29368626, Table S3). In vitro functional studies suggest that this variant does not impact BRIP1 protein function (Moyer et al. 2019. PubMed ID: 31822495). This variant is reported in 0.096% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128169/). This variant could be benign. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.61

D;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

5.7

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.9

N;.

REVEL

Uncertain

0.58

Sift

Benign

0.13

T;.

Sift4G

Benign

0.095

T;T

Polyphen

1.0

D;.

Vest4

0.73

MVP

0.96

MPC

0.64

ClinPred

0.83

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.73

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over