NM_032043.3:c.1018C>T

Variant names:

Variant summary

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

The NM_032043.3(BRIP1):c.1018C>T(p.Leu340Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,613,952 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. L340P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2

Conservation

PhyloP100: 6.07

Publications

7 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.1018C>T	p.Leu340Phe	missense_variant	Exon 8 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.1018C>T	p.Leu340Phe	missense_variant	Exon 8 of 20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251306

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:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000227

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111878

Other (OTH)

AF:

0.0000331

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

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:

0.0000131

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41550

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Apr 01, 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.1018C>T (p.Leu340Phe) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type (IPR006554) 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 8.1e-06 in 1613952 control chromosomes, predominantly at a frequency of 0.00025 within the East Asian subpopulation in the gnomAD database. Although, the observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing breast cancer phenotype (6.3e-05), this frequency is not significantly higher than estimated for a pathogenic variant in BRIP1 causing autosomal recessive Fanconi anemia complementation group J (8.1e-06 vs 0.0004), allowing no conclusion about variant significance. c.1018C>T has been reported in the literature in individuals affected with different types of cancers including breast cancer, esophageal squamous cell carcinoma, epithelial ovarian cancer, pancreatic ductal adenocarcinoma, biliary tract cancer, and lung cancer (Kim_2016, Kwong_2020, Deng_2019, Yao_2022, Cremin_2020, Okawa_2023, Yi_2024). These reports do not provide unequivocal conclusions about association of the variant with breast cancer or Fanconi Anemia Complementation Group J. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity in in vitro assays but retains the ability to restore wild type-level protein activity in cell-based assays (Odermatt_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32255556, 30833958, 27107905, 26790966, 32068069, 32542039, 36243179, 26709662, 35186721, 37885353). ClinVar contains an entry for this variant (Variation ID: 407835). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Aug 13, 2019

Leiden Open Variation Database

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Sep 01, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 24, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces leucine with phenylalanine at codon 340 of the BRIP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26790966; DOI: 10.1016/j.gimo.2023.100579) and in an individual affected with esophageal squamous cell carcinoma (PMID: 30833958). In a large breast cancer case-control meta-analysis, this variant has been observed in 4/60466 cases and 7/53461 unaffected controls (PMID: 33471991). In a pancreatic cancer case-control study, this variant was absent in 1005 cases and observed in 14/23705 controls (PMID: 32980694). In a prostate cancer case-control study, this variant was observed in 4/7636 cases and 9/12366 controls (PMID: 31214711). This variant has also been identified in 3/251306 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. -

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 leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 340 of the BRIP1 protein (p.Leu340Phe). This variant is present in population databases (rs755796609, gnomAD 0.02%). This missense change has been observed in individual(s) with biliary tract cancer, breast cancer, esophageal cancer, pancreatic cancer, and/or prostate cancer (PMID: 26790966, 30833958, 31214711, 32068069, 32255556). ClinVar contains an entry for this variant (Variation ID: 407835). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The BRIP1 c.1018C>T variant is predicted to result in the amino acid substitution p.Leu340Phe. This variant has been reported as a variant of uncertain significance in individuals with multiple different cancer types; however, no follow-up studies have confirmed its pathogenicity (Deng et al. 2019. PubMed ID: 30833958; Kim et al. 2016. PubMed ID: 26790966; Yin et al. 2022. PubMed ID: 35171259; Okawa et al. 2022. PubMed ID: 36243179). This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD. It has conflicting classifications of uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/407835/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Fanconi anemia complementation group J

Uncertain:1

Nov 14, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:1

Dec 28, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with breast, pancreatic, prostate, and other cancers, as well as in unaffected controls (PMID: 26790966, 28873162, 30833958, 31214711, 32255556, 32068069); Published functional in vitro studies demonstrate ability to rescue BRIP1 knockout cellular phenotypes similar to wild type with a moderate defect (PMID: 32542039); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26790966, 27150160, 24336570, 26709662, 28873162, 30833958, 31214711, 27107905, Padeganeh2023[Poster], 35186721, 32255556, 32068069, 32542039, 35171259, 36243179, 37885353) -

Familial ovarian cancer

Uncertain:1

Jun 17, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast

Uncertain:1

Feb 28, 2024

Baylor Genetics

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

0.19

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.80

T;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

6.1

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.9

D;.

REVEL

Pathogenic

0.66

Sift

Benign

0.046

D;.

Sift4G

Uncertain

0.052

T;T

Polyphen

0.98

D;.

Vest4

0.43

MutPred

0.74

Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);

MVP

0.97

MPC

0.30

ClinPred

0.59

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.54

gMVP

0.71

Mutation Taster

=52/48

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over