rs786201819

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032043.3(BRIP1):ā€‹c.1040T>Cā€‹(p.Leu347Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,914 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 (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L347I) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

5
10
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 6.61
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRIP1NM_032043.3 linkuse as main transcriptc.1040T>C p.Leu347Pro missense_variant 8/20 ENST00000259008.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRIP1ENST00000259008.7 linkuse as main transcriptc.1040T>C p.Leu347Pro missense_variant 8/201 NM_032043.3 P2Q9BX63-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152144
Hom.:
0
Cov.:
32
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
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461770
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727200
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152144
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74332
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 10, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 08, 2022The p.L347P variant (also known as c.1040T>C), located in coding exon 7 of the BRIP1 gene, results from a T to C substitution at nucleotide position 1040. The leucine at codon 347 is replaced by proline, an amino acid with similar properties. This alteration was detected in 1/1824 patients with triple negative breast cancer, who were unselected for a family history of breast or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11). However, in two other studies this variant has not been observed in breast or ovarian cases but has been seen in controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107; Weber-Lassalle N et al. Breast Cancer Res. 2018 Jan;20:7). In one study, this alteration was classified as a loss of function mutation based on its failure to confer resistance to either cisplatin or mitomycin C treatment (Calvo JA et al. Mol Cancer Res, 2021 06;19:1015-1025). This amino acid position is well 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. -
Familial cancer of breast Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsFeb 18, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Feb 28, 2023This 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. -
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioDec 15, 2022- -
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 17, 2024This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 347 of the BRIP1 protein (p.Leu347Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 184958). 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) has been performed at Invitae 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: 33619228). 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. -
Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylAug 22, 2016- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 01, 2024Not 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; Published functional studies suggest a damaging effect: failed to confer resistance to inter-strand crosslink-inducing agents (PMID: 33619228); Observed in individuals with breast cancer, but also in healthy control subjects (PMID: 29368626, 26315354, 25452441); This variant is associated with the following publications: (PMID: 25452441, 26315354, 29368626, 33619228) -
Ovarian neoplasm Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylAug 22, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.63
D;.
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.79
T;T
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Uncertain
-0.11
T
MutationAssessor
Uncertain
2.5
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-3.9
D;.
REVEL
Pathogenic
0.74
Sift
Benign
0.030
D;.
Sift4G
Benign
0.064
T;T
Polyphen
1.0
D;.
Vest4
0.76
MutPred
0.76
Gain of disorder (P = 0.009);Gain of disorder (P = 0.009);
MVP
0.96
MPC
0.85
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.72
gMVP
0.84

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs786201819; hg19: chr17-59878714; API