17-61861539-T-C

Position:

chr17-61861539-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_032043.3(BRIP1):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000081 in 1,605,014 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

BRIP1
NM_032043.3 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7

Conservation

PhyloP100: 3.46

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 links:

BRIP1 (HGNC:):

BRIP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PP5

Variant 17-61861539-T-C is Pathogenic according to our data. Variant chr17-61861539-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187378.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	2/20	ENST00000259008.7	NP_114432.2	Q9BX63-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	2/20	1	NM_032043.3	ENSP00000259008.2		Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251168

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000826

AC:

AN:

1452836

Hom.:

Cov.:

AF XY:

0.00000968

AC XY:

AN XY:

723488

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000543

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast;C1836860:Fanconi anemia complementation group J

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	This sequence change affects the initiator methionine of the BRIP1 mRNA. The next in-frame methionine is located at codon 4. This variant is present in population databases (rs764585550, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 187378). 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. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2023	The p.M1? variant (also known as c.1A>G), located in coding exon 1 of the BRIP1 gene, results from an A to G substitution at nucleotide position 1. This alters the methionine at the translation initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however there are alternate in-frame methionines 3 and 27 amino acids from the initiation site and the significance of the N-terminus for this protein is not well established. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 07, 2023	This variant alters the methionine at codon 1 in the BRIP1 protein and is expected to disrupt protein translation initiation. However, in-frame methionines located at codons 4, 28, or 29 could potentially serve as alternate translation start sites. To our knowledge, functional studies have not been performed to determine whether these methionines are utilized for translation initiation. This variant has been reported in individuals affected with breast cancer (PMID: 32091409, 33471991). In an international breast cancer case-control meta-analysis, this variant was detected in 9/60466 cases and 3/53461 unaffected controls (PMID: 33471991; OR=2.653, 95%CI 0.718 to 9.799, p-value=0.155). This variant has been identified in 4/251168 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. -

Genetic non-acquired premature ovarian failure

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University

Dec 01, 2021

- -

Ovarian cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Fanconi anemia complementation group J

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 27, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2023

Initiation codon variant in a gene for which a downstream in-frame ATG could serve as an alternate initiator codon that may result in a functional protein; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer (Chen et al., 2020); This variant is associated with the following publications: (PMID: 35032816, 32091409) -

Ovarian neoplasm

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 27, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Benign

0.67

DEOGEN2

Benign

0.31

T;.;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

-0.16

PROVEAN

Benign

-1.7

N;.;.

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

0.98

D;.;.

Vest4

0.84

MutPred

0.97

Gain of catalytic residue at M1 (P = 0.0931);Gain of catalytic residue at M1 (P = 0.0931);Gain of catalytic residue at M1 (P = 0.0931);

MVP

0.89

ClinPred

0.93

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.80

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over