17-61801281-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032043.3(BRIP1):​c.1112A>G​(p.Tyr371Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,582 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 (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.27
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_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRIP1NM_032043.3 linkc.1112A>G p.Tyr371Cys 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
BRIP1ENST00000259008.7 linkc.1112A>G p.Tyr371Cys missense_variant Exon 8 of 20 1 NM_032043.3 ENSP00000259008.2 Q9BX63-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461582
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Oct 19, 2020
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces tyrosine with cysteine at codon 371 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. -

Sep 22, 2020
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Y371C variant (also known as c.1112A>G), located in coding exon 7 of the BRIP1 gene, results from an A to G substitution at nucleotide position 1112. The tyrosine at codon 371 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Oct 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 371 of the BRIP1 protein (p.Tyr371Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 407853). 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 expected to disrupt BRIP1 protein function with a positive predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
D;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
0.39
D
MutationAssessor
Pathogenic
3.3
M;M
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-8.2
D;.
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;.
Vest4
0.93
MutPred
0.86
Gain of catalytic residue at L372 (P = 0.0101);Gain of catalytic residue at L372 (P = 0.0101);
MVP
0.94
MPC
0.77
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.93
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1060501768; hg19: chr17-59878642; API