chr17-61715993-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_032043.3(BRIP1):​c.2450A>G​(p.Tyr817Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,866 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. Y817H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

16
2
1

Clinical Significance

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

Conservation

PhyloP100: 7.45

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_pathogenic. The variant received 6 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_032043.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRIP1NM_032043.3 linkc.2450A>G p.Tyr817Cys missense_variant Exon 17 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.2450A>G p.Tyr817Cys missense_variant Exon 17 of 20 1 NM_032043.3 ENSP00000259008.2 Q9BX63-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1456866
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
724560
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33406
American (AMR)
AF:
0.00
AC:
0
AN:
44530
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26036
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39420
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85214
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53142
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5748
European-Non Finnish (NFE)
AF:
9.02e-7
AC:
1
AN:
1109248
Other (OTH)
AF:
0.00
AC:
0
AN:
60122
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

Ovarian cancer;C1836860:Fanconi anemia complementation group J Uncertain:1
Dec 14, 2017
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1
Apr 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 817 of the BRIP1 protein (p.Tyr817Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 548822). 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 cancer of breast Uncertain:1
Feb 27, 2023
Myriad Genetics, Inc.
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.62
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.4
H;H
PhyloP100
7.4
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-8.5
D;.
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;.
Vest4
0.96
MutPred
0.56
Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MVP
1.0
MPC
0.77
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.91
gMVP
0.89
Mutation Taster
=61/39
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: rs1555580828; hg19: chr17-59793354; API