17-61743048-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032043.3(BRIP1):c.2344A>G(p.Ile782Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I782T) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 0.721

Publications

3 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11720559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3 link	c.2344A>G	p.Ile782Val	missense_variant	Exon 16 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 link	c.2344A>G	p.Ile782Val	missense_variant	Exon 16 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

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

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251332

AF XY:

0.0000147

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1461726

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000387

AC:

AN:

1111912

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:4

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 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. -

Dec 06, 2018

Division of Medical Genetics, University of Washington

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2344A>G missense variant has been identified in individuals with breast cancer and pancreatic cancer (Easton 2016, Shindo 2017), but has not to our knowledge been reported in an individual with ovarian cancer. The vast majority of pathogenic variants reported in the BRIP1 gene to date are truncating variants. The c.2344A>G variant has an allele frequency of 0.000008 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/). Thus, it is unknown at this time whether this variant increases cancer risk. -

not provided

Uncertain:2

Oct 12, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population, 0.000008 (2/251332 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast cancer and in controls (PMID: 26921362 (2016)) as well as in individuals affected with pancreatic cancer (PMID: 28767289 (2017)). One functional study described this variant as a hypomorph due to the modest reduction in cellular growth observed after high-dose treatment with a DNA damaging agent (PMID: 31822495 (2020)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jun 17, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast or pancreatic cancer (Easton 2016, Shindo 2017); Published functional studies are inconclusive: lack of cisplatin sensitivity but intermediate mitomycin C sensitivity (Moyer 2020); This variant is associated with the following publications: (PMID: 24123366, 26921362, 28767289, 27535533, 31822495) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Sep 13, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.I782V variant (also known as c.2344A>G), located in coding exon 15 of the BRIP1 gene, results from an A to G substitution at nucleotide position 2344. The isoleucine at codon 782 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in cohorts of breast, pancreatic, and ovarian cancer patients, as well as in a control (Easton DF et al. J Med Genet, 2016 05;53:298-309; Shindo K et al. J. Clin Oncol, 2017 Oct;35:3382-3390; Moyer CL et al. Cancer Res, 2020 02;80:857-867). In an inter-strand cross link damage survival assay, the p.I782V alteration was found to be functionally hypomorphic (Moyer CL et al. Cancer Res, 2020 02;80:857-867). 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. -

Dec 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces isoleucine with valine at codon 782 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function. A functional study has reported that this variant resulted in hymomorphic activity in a mitomycin C sensitivity assay (PMID: 31822495). This variant has been detected in individuals affected with pancreatic cancer (PMID: 28767289, 32659497) and in 10/101759 breast cancer and 1/15587 ovarian cancer cases (PMID: 31822495). This variant also has been reported in the general population (PMID: 31822495) and in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/17-59820409-T-C). A breast cancer case-control meta-study has detected this variant in 3/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRIP1_000419). This variant has been identified in 2/251332 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:1

Nov 16, 2023

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.2344A>G (p.Ile782Val) results in a conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of 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 8e-06 in 251332 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2344A>G has been reported in the literature, primarily as a VUS in settings of multigene panel testing, in individuals affected with pancreatic, breast, and ovarian cancers, and also in at least one control individual (e.g. Easton_2016, Shindo_2017, Moyer_2020, Bhai_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A functional study evaluated the effect of the variant using a transient DNA damage-based rescue assay and categorized the variant as hypomorphic (Moyer_2020); however, this does not allow strong conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 31822495, 28767289, 26921362). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters 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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 782 of the BRIP1 protein (p.Ile782Val). This variant is present in population databases (rs142806416, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and/or pancreatic cancer (PMID: 26921362, 28767289, 32659497, 34326862). ClinVar contains an entry for this variant (Variation ID: 142346). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on BRIP1 function (PMID: 31822495). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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

Uncertain:1

Aug 30, 2016

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. -

Fanconi anemia complementation group J

Uncertain:1

Aug 30, 2016

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Familial ovarian cancer

Uncertain:1

Jan 16, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.81

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

-0.73

N;N

PhyloP100

0.72

PrimateAI

Benign

0.32

PROVEAN

Benign

0.38

N;.

REVEL

Benign

0.28

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.011

B;.

Vest4

0.14

MVP

0.67

MPC

0.17

ClinPred

0.026

GERP RS

-1.2

Varity_R

0.025

gMVP

0.31

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over