rs752309409

Positions:

• chr17-61808634-G-A
• chr17-61808634-G-C
• chr17-61808634-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_032043.3(BRIP1):​c.751C>T​(p.Arg251Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R251H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 U:1
• Conservation: PhyloP100: 9.21

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_032043.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 17-61808634-G-A is Pathogenic according to our data. Variant chr17-61808634-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61808634-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.751C>T	p.Arg251Cys	missense_variant	7/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.751C>T	p.Arg251Cys	missense_variant	7/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251170 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135740

Gnomad AFR exome AF: 0.0000615

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461772 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727186

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152046 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74276

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 27, 2022	This missense variant replaces arginine with cysteine at codon 251 in the helicase domain 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 the mutant protein shows no DNA helicase activity, reduced ATP binding activity, reduced DNA-dependent ATPase activity, and failed to complement BRIP1-null cell line (PMID: 24573678, 27107905). This variant has been reported in two homozygous individuals affected with Fanconi anemia (PMID: 27427815, 31558676), as well as in an individual affected with Fanconi anemia in compound heterozygous state with a deleterious p.His396Asp variant (PMID: 23613520) (ClinVar variation ID: 659729). In a large breast cancer case-control study, this variant has been observed in 3/60463 cases and 2/53459 controls (PMID: 33471991 - Leiden Open Variation Database DB-ID BRIP1_000010). This variant has also been reported in 2 unaffected control individuals in pancreatic and prostate cancer case-control studies and absent in affected individuals (PMID: 31214711, 32980694). This variant has been identified in 3/251170 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this variant has been shown to impair BRIP1 protein function. The observation of this variant in biallelic individuals affected with autosomal recessive Fanconi anemia indicates that this variant contributes to disease. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 07, 2022	The p.R251C pathogenic mutation (also known as c.751C>T), located in coding exon 6 of the BRIP1 gene, results from a C to T substitution at nucleotide position 751. The arginine at codon 251 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in one individual diagnosed with Fanconi anemia along with a second alteration in BRIP1 (Chandrasekharappa SC et al. Blood 2013 May;121(22):e138-48). This alteration was also identified the homozygous state in a cohort of Israeli patients diagnosed with Fanconi anemia (Steinberg-Shemer O et al. Haematologica. 2019 Sep), as well as in 55-year-old identical twins, both affected with cancer and a late-onset and less severe form of Fanconi anemia, leading the authors to speculate that this may be a hypomorphic allele (Stevens H et al. Am. J. Hematol. 2016 Dec;91:1273-1276). This alteration has been reported in 0/7636 unselected prostate cancer patients and 1/12,366 male controls of Japanese ancestry (Momozawa Y et al. J. Natl. Cancer Inst. 2019 Jun). Functional studies showed this alteration to be deficient in helicase activity, as well as DNA and ATP binding. In addition, cells expressing this alteration showed increased cell death in response to DNA damaging agents compared to wild type (Guo M et al. J. Biol. Chem. 2014 Apr;289:10551-65). Structural analysis indicates that p.R251C likely disrupts ligand binding in a functionally significant and sensitive region (Ambry internal data, He Y et al. EMBO Rep. 2010 Mar;11:180-6; He Y et al. Nature. 2016 05;533:359-65). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Oct 18, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 22, 2023	- -

Familial cancer of breast Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Feb 13, 2024	PS3, PM1, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 28, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24573678]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23613520, 31586946]. -

Fanconi anemia complementation group J Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 19, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2022	Variant summary: BRIP1 c.751C>T (p.Arg251Cys) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type domain 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 1.2e-05 in 251170 control chromosomes. c.751C>T has been reported in the literature in multiple individuals affected with Fanconi Anemia Complementation Group J in the homozygous and compound heterozygous state (Chandrasekharappa_2013, Stevens_2016, Steinberg-Shermer_2020, Bogliolo_2020) as well as in patients with breast cancer in the heterozygous state (e.g. Schrader_2016). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was shown to abolish DNA helicase activity and DNAprotein displacement activity (Guo_2014). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five submitters classified the variant as likely pathogenic/pathogenic while one classified the variant as VUS. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 16, 2022	The frequency of this variant in the general population, 0.000012 (3/251170 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26921362 (2016), 26556299 (2016)), Fanconi anemia (PMID: 31586946 (2020), 31558676 (2020), 27427815 (2016), 23613520 (2013)), and pancreatic cancer (PMID: 31214711 (2020)). In a large breast cancer association study, this variant was reported in individuals affected with breast cancer and in healthy controls (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/BRIP1). Functional studies reported this variant to be damaging to cell survival, DNA helicase activity, DNA binding, ATP hydrolysis activity and binding, as well as DNA repair functions (PMID: 27107905 (2016), 24573678 (2014)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2023	Observed in the homozygous and compound heterozygous state in individuals with Fanconi anemia referred for genetic testing at GeneDx and in the published literature (Chandrasekharappa et al., 2013; Stevens et al., 2016; Bogliolo et al., 2020); Observed in individuals with breast cancer (Easton et al., 2016; Schrader et al., 2016); Published functional studies demonstrate a damaging effect: deficient in vitro complementation in a BRIP1 null cell line and reduced DNA binding (Guo et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25374583, 31586946, 33028645, 23613520, 28235761, 27107905, 26596371, 26921362, 26556299, 27427815, 33137625, 31558676, 31214711, 24573678, 19763819, 22692731, 11301010, 33471991) -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 251 of the BRIP1 protein (p.Arg251Cys). This variant is present in population databases (rs752309409, gnomAD 0.0009%). This missense change has been observed in individuals with breast cancer and/or Fanconi anemia (PMID: 23613520, 26556299, 27427815, 31558676, 31586946). ClinVar contains an entry for this variant (Variation ID: 185848). 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%. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 24573678, 27107905). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Uncertain:1

Uncertain significance, flagged submission

clinical testing

Counsyl

Oct 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.5	D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.86		Loss of MoRF binding (P = 0.0047);Loss of MoRF binding (P = 0.0047);
MVP		1.0
MPC		0.80
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.93

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

Other links and lift over

dbSNP: rs752309409; hg19: chr17-59885995; COSMIC: COSV99371257;