rs587780239

chr17-61715974-C-Achr17-61715974-C-Gchr17-61715974-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM5 PP3

The NM_032043.3(BRIP1):c.2469G>T(p.Arg823Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,605,648 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. R823G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12 B:1 O:1
• Conservation: PhyloP100: 0.817

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 Uncertain_significance. Variant got 5 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, 16 uncertain in NM_032043.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-61715976-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 631133.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.2469G>T	p.Arg823Ser	missense_variant	17/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.2469G>T	p.Arg823Ser	missense_variant	17/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151952 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

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: 0.0000480 AC: 12 AN: 249930 Hom.: 0 AF XY: 0.0000666 AC XY: 9 AN XY: 135170

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000337 AC: 49 AN: 1453696 Hom.: 0 Cov.: 30 AF XY: 0.0000360 AC XY: 26 AN XY: 723204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000833

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151952 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74204

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12 Benign:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 04, 2022	The p.R823S variant (also known as c.2469G>T), located in coding exon 16 of the BRIP1 gene, results from a G to T substitution at nucleotide position 2469. The arginine at codon 823 is replaced by serine, an amino acid with dissimilar properties. This variant was reported in 1/1212 breast cancer patients with a family history of breast or ovarian cancer, but was not seen in 2081 controls (Seal S et al. Nat. Genet. 2006 Nov;38:1239-41). It was also reported in 1/1142 pancreatic cancer patients (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390). This variant was also observed in 2/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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	May 06, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2024	This missense variant replaces arginine with serine at codon 823 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 17033622), pancreatic cancer (PMID: 28767289, 32659497) and ovarian cancer (Collet 2015, DOI: 10.3934/genet.2015.4.263), but also in control individuals (PMID: 29368626). This variant has been identified in 12/249930 chromosomes (10/10054 Ashkenazi Jewish 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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jun 23, 2017	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of pancreatic or breast cancer (Shindo et al., 2017; Hu et al., 2020; Lerner-Ellis et al., 2021); This variant is associated with the following publications: (PMID: 17033622, 28767289, 29368626, 32659497, 11301010, 32885271) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 04, 2023	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 17033622 (2006), 32885271 (2021) 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRIP1)), and pancreatic cancer (PMID: 28767289 (2017), 32659497 (2020)). This variant has also been reported in unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRIP1)). The frequency of this variant in the general population, 0.00099 (10/10054 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 04, 2016	- -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 21, 2022	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 823 of the BRIP1 protein (p.Arg823Ser). This variant is present in population databases (rs587780239, gnomAD 0.1%). This missense change has been observed in individual(s) with breast cancer or pancreatic cancer (PMID: 17033622, 28767289). ClinVar contains an entry for this variant (Variation ID: 128173). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 04, 2022	- -

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 02, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2023	- -

Malignant tumor of breast Uncertain:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 01-09-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRIP1 p.Arg823Ser variant was identified in 2 of 4132 proband chromosomes (frequency: 0.0005) from individuals or families with breast or pancreatic cancer and was not identified in 4162 control chromosomes from healthy individuals (Seal 2006, Shindo 2017). The variant was also identified in dbSNP (ID: rs587780239) as "With Likely benign, Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics and three other submitters; and as likely benign by True Health Diagnostics). The variant was identified in control databases in 12 of 244892 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 111146 chromosomes (freq: 0.00002) and Ashkenazi Jewish in 10 of 9830 chromosomes (freq: 0.001), while the variant was not observed in the African, Other, Latino, East Asian, Finnish, or South Asian populations. The p.Arg823 residue is conserved in mammals but not in more distantly related organisms, although 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

Neoplasm of ovary;C1836860:Fanconi anemia complementation group J Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jun 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.63		Loss of MoRF binding (P = 0.0155);Loss of MoRF binding (P = 0.0155);
MVP		0.99
MPC		0.73
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs587780239; hg19: chr17-59793335; COSMIC: COSV52009547;