17-61744570-G-A

Position:

chr17-61744570-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PP3_StrongPP5_Strong

The ENST00000259008.7(BRIP1):c.2119C>T(p.Arg707Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,288 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. R707G) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

BRIP1
ENST00000259008.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:9

Conservation

PhyloP100: 7.44

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

PP5

Variant 17-61744570-G-A is Pathogenic according to our data. 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}. Variant chr17-61744570-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3 linkuse as main transcript	c.2119C>T	p.Arg707Cys	missense_variant	15/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7 linkuse as main transcript	c.2119C>T	p.Arg707Cys	missense_variant	15/20	1	NM_032043.3	ENSP00000259008	P2	Q9BX63-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151996

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251042

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135694

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461292

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726996

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74220

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000307

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 25, 2023	- -
Likely pathogenic, flagged submission	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with complementation group J Fanconi anaemia (MIM#609054), and susceptibility to early-onset breast cancer (MIM#114480) and ovarian cancer (National Comprehensive Cancer Network guidelines). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic pathogenic variants are associated with complementation group J Fanconi anaemia, while monoallelic pathogenic variants are associated with increased susceptibility to cancer. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 (8 heterozygotes, 0 homozygotes). (SP) 0309 - Two alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated motif IV within the helicase core domain (PMID: 29788478). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Alternative changes p.(Arg707His), p.(Arg707Ser) and p.(Arg707Gly) have been reported as VUS (ClinVar, PMID: 26976419). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported in an individual with Fanconi anaemia who also has another missense variant (PMID: 16116423). It has also been found once as a germline variant in an ovarian cancer patient cohort (PMID: 31822495). In addition, it has been reported in ClinVar multiple times as VUS and once as likely pathogenic. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies showed the R707C protein had reduced DNA binding, ATPase and helicase activities (PMID: 29788478). The R707C protein failed to rescue cisplatin or mitomycin sensitivity, but was able to confer resistance to aphidicolin, telomestatin and bleomycin. It was regarded as a hypomorphic variant in PMID: 33619228. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 08, 2021	This missense variant replaces arginine with cysteine 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). Functional studies have shown that this variant protein displays decreased helicase activity and fails to restore resistance to DNA interstrand crosslink (ICL)-inducing agents in BRIP1-deficient cells (PMID: 29788478, 33619228). This variant has been reported in an individual affected with Fanconi anemia complementation group J (PMID: 16116423). This variant has also been reported in individuals affected with breast cancer and ovarian cancer (PMID: 31822495, 33471991). This variant has been identified in 8/282390 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 submitter	clinical testing	Ambry Genetics	May 28, 2024	The p.R707C variant (also known as c.2119C>T), located in coding exon 14 of the BRIP1 gene, results from a C to T substitution at nucleotide position 2119. The arginine at codon 707 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in multiple individuals diagnosed with Fanconi Anemia complementation group J (FA-J); however, limited information was provided (Levitus M et al. Nat. Genet. 2005 Sep;37:934-5; George M et al. Hum Mutat. 2021 Dec;42:1648-1665). This alteration was detected in 1/1,199 ovarian cancer cases (Moyer CL et al. Cancer Res. 2020 Feb;80:857-867). In addition, functional studies suggest this variant partially impairs helicase activity compared to wild type (Bharti SK et al. Nucleic Acids Res. 2018 07;46:6238-6256). 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 24, 2021	- -

Fanconi anemia complementation group J

Pathogenic:1

Pathogenic, flagged submission

curation

Leiden Open Variation Database

Feb 07, 2011

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 02, 2024

Variant summary: BRIP1 c.2119C>T (p.Arg707Cys) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251042 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2119C>T has been reported in the literature in individuals affected with Fanconi Anemia (Levitus_2005, George_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Complementation Group J. At least one publication reports experimental evidence evaluating an impact on protein function and evaluated the variant as a hypomorphic change, however, does not allow convincing conclusions about the variant effect (Calvo_2021). The following publications have been ascertained in the context of this evaluation (PMID: 33619228, 34585473, 16116423). ClinVar contains an entry for this variant (Variation ID: 234570). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 707 of the BRIP1 protein (p.Arg707Cys). This variant is present in population databases (rs764803896, gnomAD 0.007%). This missense change has been observed in individual(s) with Fanconi anemia, ovarian cancer (PMID: 16116423, 31822495). ClinVar contains an entry for this variant (Variation ID: 234570). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects BRIP1 function (PMID: 29788478). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

This variant is denoted BRIP1 c.2119C>T at the cDNA level, p.Arg707Cys (R707C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was observed in an individual with Fanconi Anemia-J who also had a second BRIP1 missense variant and weak BRIP1 protein expression on Western blot analysis (Levitus 2005). However, as phase was not described, we cannot be certain that Arg707Cys was in trans with the second missense variant. In vitro functional assays suggests this variant partially impairs helicase activity compared to wild type (Bhari 2018). BRIP1 Arg707Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the helicase domain (Cantor 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRIP1 Arg707Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Jul 08, 2024

According to the ACMG SVI adaptation criteria we chose these criteria: PS3 (supporting pathogenic): funktionelle Analysen Bharti et al. 2018; Calvo et al. 2021, PP3 (supporting pathogenic): Revel 0,854, aber SIFT: neutral, ... nach Canvog: PP3 nur als Supp zu werten => Bewertungsstärke? -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.72

D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.24

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.3

D;.

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.85

MVP

0.98

MPC

0.80

ClinPred

0.83

GERP RS

5.5

Varity_R

0.86

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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