rs786201632

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The ENST00000259008.7(BRIP1):ā€‹c.2885T>Cā€‹(p.Ile962Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. I962V) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

BRIP1
ENST00000259008.7 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: -0.199
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 Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.059421062).
BP6
Variant 17-61685856-A-G is Benign according to our data. Variant chr17-61685856-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184706.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRIP1NM_032043.3 linkuse as main transcriptc.2885T>C p.Ile962Thr missense_variant 19/20 ENST00000259008.7 NP_114432.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRIP1ENST00000259008.7 linkuse as main transcriptc.2885T>C p.Ile962Thr missense_variant 19/201 NM_032043.3 ENSP00000259008 P2Q9BX63-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
33
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
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250396
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135452
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460144
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726476
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74370
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:
0.0000565
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMay 08, 2019- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 26, 2024This 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 25, 2022Variant summary: BRIP1 c.2885T>C (p.Ile962Thr) results in a non-conservative amino acid change in 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 4e-06 in 250396 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2885T>C has been reported in the literature citing the ClinVar database classification as a VUS (as of May-2019) among a discovery cohort of individuals affected with early onset breast cancer (example, Moyer_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -
BRIP1-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 05, 2024The BRIP1 c.2885T>C variant is predicted to result in the amino acid substitution p.Ile962Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184706/). 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 submitterclinical testingCounsylJul 14, 2017- -
Familial cancer of breast Uncertain:1
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. -
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 24, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.077
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
1.7
DANN
Benign
0.58
DEOGEN2
Benign
0.090
T;.
Eigen
Benign
-0.94
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.050
N
LIST_S2
Benign
0.37
T;T
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.059
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.0
L;L
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.17
N;.
REVEL
Benign
0.058
Sift
Benign
0.68
T;.
Sift4G
Benign
0.42
T;T
Polyphen
0.0050
B;.
Vest4
0.084
MutPred
0.16
Gain of glycosylation at I962 (P = 0.0179);Gain of glycosylation at I962 (P = 0.0179);
MVP
0.76
MPC
0.21
ClinPred
0.0082
T
GERP RS
1.1
Varity_R
0.030
gMVP
0.11

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: rs786201632; hg19: chr17-59763217; API