rs28997569

chr17-61808595-G-Achr17-61808595-G-Cchr17-61808595-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_032043.3(BRIP1):c.790C>T(p.Arg264Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,613,856 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:19 O:1
• Conservation: PhyloP100: 3.66

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041837633).
• BP6: Variant 17-61808595-G-A is Benign according to our data. Variant chr17-61808595-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128195.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=16, not_provided=1, Uncertain_significance=3}. Variant chr17-61808595-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.790C>T	p.Arg264Trp	missense_variant	7/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.790C>T	p.Arg264Trp	missense_variant	7/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes AF: 0.00100 AC: 152 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000828 AC: 208 AN: 251076 Hom.: 0 AF XY: 0.000877 AC XY: 119 AN XY: 135670

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00118 AC: 1719 AN: 1461734 Hom.: 3 Cov.: 31 AF XY: 0.00117 AC XY: 853 AN XY: 727172

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000999 AC: 152 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74390

Gnomad4 AFR AF: 0.000844

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00101

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000708 AC: 86

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:19 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	Mar 28, 2018	The BRIP1 variant designated as NM_032043.2:c.790C>T (p.Arg264Trp) is now classified as likely benign. The variant is present in approximately 1 in 500 individuals in European and African populations (exac.broadinstitute.org). This population frequency is not consistent with a high-risk cancer variant. In addition, there are no reports of pathogenic missense variants in this BRIP1 protein domain. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 128195). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BRIP1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Uncertain:1 Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2015	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 07, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 22, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 08, 2021	- -

Fanconi anemia complementation group J Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Malignant tumor of breast Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRIP1 p.Arg264Trp variant was identified in 55 of 46810 proband chromosomes (frequency: 0.001) from Italian, American, British and Colombian individuals or families with a wide spectrum of cancers (in population based studies, unselected for family history): BRCA1/2 negative, male/female breast cancer, prostate cancer, ovarian cancer, Lynch syndrome associated cancer and/or polyps, CRC, pancreatic cancer, hereditary prostate cancer and Fanconi anemia; and was present in 44 of 29724 control chromosomes (frequency: 0.001) from healthy individuals (Silvestri_2011_21165771, Bodian_2014_24728327, Hu_2016_26483394, Yurgelun_2015_25980754, Tung_20016_26976419, Seal_2006_17033622, Easton_2016_26921362, Levitus_2005_16116423, Pearlman_2016_27978560, Ramus_2015_26315354, Cock-Rada_2017_28528518, Ray_2009_19935797). In one prostate cancer family, the variant was identified in two out of three cases and was not present in the unaffected brother of the proband (Ray_2009_19935797). In 1 male proband with breast cancer, diagnosed at 76 yrs of age, DNA extracted from the micro-dissected breast tumor sample showed that no loss of the wild-type allele had occurred in tumor cells (Silvestri_2011_21165771). The variant was identified in dbSNP (ID: rs28997569) “With Likely benign allele”, ClinVar (classified likely benign by Invitae, Ambry Genetics, Genetic Services Laboratory (University of Washington), Counsyl, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, and GeneDx, and classification not provided by ITMI), Clinvitae (5x) and Zhejiang Colon Cancer Database, and was not identified in Cosmic or MutDB. The variant was also identified in control databases in 229 of 276746 chromosomes at a frequency of 0.0008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 17 of 24030 chromosomes (freq: 0.0007), “Other” in 11 of 6452 chromosomes (freq: 0.002), Latino in 15 of 34408 chromosomes (freq: 0.0004), European Non-Finnish in 145 of 126288 chromosomes (freq: 0.001), Ashkenazi Jewish in 28 of 10142 chromosomes (freq: 0.003), European Finnish in 7 of 25786 chromosomes (freq: 0.0003), and South Asian in 6 of 30782 chromosomes (freq: 0.0002); it was not observed in the East Asian population. The p.Arg264 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Center of Medical Genetics and Primary Health Care	-	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jun 21, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Neoplasm of ovary Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Jul 18, 2016

- -

BRIP1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.042	T;T
MetaSVM	Uncertain	-0.0027	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	0.80	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.55
MVP		0.96
MPC		0.67
ClinPred		0.032	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28997569; hg19: chr17-59885956; COSMIC: COSV52000602;