rs878855138

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7

The NM_032043.3(BRIP1):​c.1368T>C​(p.Leu456Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

BRIP1
NM_032043.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.321

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
Variant 17-61793702-A-G is Benign according to our data. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626. Variant chr17-61793702-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 241626.
BP7
Synonymous conserved (PhyloP=0.321 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRIP1NM_032043.3 linkc.1368T>C p.Leu456Leu synonymous_variant Exon 10 of 20 ENST00000259008.7 NP_114432.2 Q9BX63-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRIP1ENST00000259008.7 linkc.1368T>C p.Leu456Leu synonymous_variant Exon 10 of 20 1 NM_032043.3 ENSP00000259008.2 Q9BX63-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
248106
AF XY:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Benign:2
Jul 19, 2017
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 14, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2
Jan 15, 2016
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. -

Nov 30, 2017
Color Diagnostics, LLC DBA Color Health
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Oct 04, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The BRIP1 c.1368T>C (p.Leu456=) synonymous variant has not been reported in individuals with BRIP1-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect BRIP1 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant. -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Benign:1
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

BRIP1-related disorder Benign:1
May 16, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial cancer of breast Benign:1
Aug 27, 2024
Myriad Genetics, Inc.
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.55
CADD
Benign
7.3
DANN
Benign
0.80
PhyloP100
0.32
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs878855138; hg19: chr17-59871063; API