rs200313471

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3

The ENST00000259008.7(BRIP1):​c.2120G>T​(p.Arg707Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,344 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R707C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

BRIP1
ENST00000259008.7 missense

Scores

9
9
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.42
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 7 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in ENST00000259008.7
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-61744570-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 234570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=9}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRIP1NM_032043.3 linkuse as main transcriptc.2120G>T p.Arg707Leu missense_variant 15/20 ENST00000259008.7 NP_114432.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRIP1ENST00000259008.7 linkuse as main transcriptc.2120G>T p.Arg707Leu missense_variant 15/201 NM_032043.3 ENSP00000259008 P2Q9BX63-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
251066
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135696
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:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461344
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726998
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:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
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 HealthDec 06, 2022This missense variant replaces arginine with leucine at codon 707 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 BRIP1-related disorders in the literature. This variant has been identified in 2/251066 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. -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 21, 2024The p.R707L variant (also known as c.2120G>T), located in coding exon 14 of the BRIP1 gene, results from a G to T substitution at nucleotide position 2120. The arginine at codon 707 is replaced by leucine, an amino acid with 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. Based on the available evidence, the clinical significance of this variant remains unclear. -
Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 707 of the BRIP1 protein (p.Arg707Leu). This variant is present in population databases (rs200313471, gnomAD 0.007%). 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: 407855). 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) performed at Invitae indicates that this missense variant is expected to disrupt BRIP1 protein function with a positive predictive value of 80%. 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. -
Familial ovarian cancer Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The BRIP1 p.Arg707Leu variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or the Zhejiang University Database. The variant was identified in dbSNP (ID: rs200313471) as “With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae and Color Genomics). The variant was identified in control databases in 2 of 245882 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 2 of 30764 chromosomes (freq: 0.0001), but not in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Arg707 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.71
D;.
Eigen
Pathogenic
0.70
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.84
D;D
MetaSVM
Uncertain
0.13
D
MutationAssessor
Uncertain
2.0
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-6.3
D;.
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0040
D;.
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.87
MutPred
0.58
Loss of loop (P = 0.0112);Loss of loop (P = 0.0112);
MVP
0.96
MPC
0.75
ClinPred
0.81
D
GERP RS
5.5
Varity_R
0.88
gMVP
0.84

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: rs200313471; hg19: chr17-59821930; API