chr17-61744456-C-T

Position:

chr17-61744456-C-T

Variant summary

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

The ENST00000259008.7(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
ENST00000259008.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17B:1

Conservation

PhyloP100: 5.69

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.2233G>A	p.Ala745Thr	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.2233G>A	p.Ala745Thr	missense_variant	15/20	1	NM_032043.3	ENSP00000259008	P2	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

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251244

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135788

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.000995

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000864

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:

0.000165

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:17Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	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 (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). 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), as well as in unaffected control individuals (PMID: 29368626, 31822495). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 19, 2022	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 studies of 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). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This alteration has also been identified in individuals diagnosed with breast and/or ovarian 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). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jun 04, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Vantari Genetics	Oct 14, 2015	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 22, 2019	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 8e-05 in 261914 control chromosomes. The observed variant frequency is approximately 1.28 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is benign. c.2233G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Ramus_2015, Maxwell_2016, Easton_2016, Catucci_2012, Weber-Lassalle_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.5946delT, p.Ser1982fsX22), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS possibly benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 11, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

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	Baylor Genetics	Mar 05, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	May 03, 2023	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. -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2024	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 supports 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) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

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

Jan 18, 2024

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, 31822495). ClinVar contains an entry for this variant (Variation ID: 128169). 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 with a negative predictive value of 80%. 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. -

BRIP1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2024

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. -

Ovarian neoplasm;C1836860:Fanconi anemia complementation group J

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Sep 06, 2017

- -

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

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

MutationTaster

Benign

1.0

D;D

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

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

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