rs4988345

Positions:

• chr17-61847211-G-A
• chr17-61847211-G-C
• chr17-61847211-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032043.3(BRIP1):​c.517C>T​(p.Arg173Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0048 in 1,613,594 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (27 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:22 O:1
• Conservation: PhyloP100: 4.08

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007955372).
• BP6: Variant 17-61847211-G-A is Benign according to our data. Variant chr17-61847211-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133761.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=2, not_provided=1, Benign=10}. Variant chr17-61847211-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00354 (539/152216) while in subpopulation NFE AF= 0.00551 (375/68024). AF 95% confidence interval is 0.00505. There are 4 homozygotes in gnomad4. There are 254 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.517C>T	p.Arg173Cys	missense_variant	6/20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.517C>T	p.Arg173Cys	missense_variant	6/20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 539 AN: 152098 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00551

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00261 AC: 656 AN: 251292 Hom.: 2 AF XY: 0.00269 AC XY: 365 AN XY: 135830

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00465

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00494 AC: 7214 AN: 1461378 Hom.: 27 Cov.: 31 AF XY: 0.00472 AC XY: 3431 AN XY: 727044

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.00234

Gnomad4 NFE exome AF: 0.00603

Gnomad4 OTH exome AF: 0.00383

GnomAD4 genome AF: 0.00354 AC: 539 AN: 152216 Hom.: 4 Cov.: 32 AF XY: 0.00341 AC XY: 254 AN XY: 74398

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00551

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00429 Hom.: 4

Bravo AF: 0.00356

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00270 AC: 328

EpiCase AF: 0.00529

EpiControl AF: 0.00462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:22 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 10, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2013	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. -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 18, 2014	This alteration is classified as 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	Nov 20, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 31, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -

Familial cancer of breast Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 01, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 18, 2018	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BRIP1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 21, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2023	- -

Fanconi anemia complementation group J Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 08, 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. -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 29, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRIP1 p.Arg173Cys variant was identified in 2 of 448 proband chromosomes (frequency: 0.004) from individuals or families with breast and ovarian cancer and was present in 2 of 246 control chromosomes (frequency: 0.008) from healthy individuals (Lewis 2005, Rutter 2003, Wong 2011). The variant was also identified in dbSNP (ID: rs4988345) as “other”; in the ClinVar database as benign by Invitae, GeneDx and Ambry genetics, and likely benign by Emory Genetics and Counsyl; and was identified in the Zhejiang Colon Cancer Database 5x. The variant was not identified in the Cosmic and MutDB databases. In addition, the variant was identified in control databases in 737 (2 homozygous) of 277072 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). One study indicates that the rare variant p.Arg173Cys impairs protein translocation to the nucleus and might modify breast cancer susceptibility. Since the minor allele for this variant is very rare (MAF= 0.008) in Centre d’Etude du Polymorphisme Humain (CEPH) samples, there was very limited evidence to confirm or refute this association using the case-control population in their current research (Song 2007). Denaturing high performance liquid chromatography (DHPLC) analysis of the coding regions of these four genes was conducted on 75 non-BRCA1/2 index cases. Variants, c.517C>T, p.Arg173Cys) and c.3411T>C, p.Thr1137=, were all found in at least one control, indicating that they are likely to be benign (Lewis 2005). The p.Arg173 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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. -

Ovarian neoplasm Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Jun 08, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.51
MVP		0.85
MPC		0.36
ClinPred		0.033	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.58

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: rs4988345; hg19: chr17-59924572; COSMIC: COSV51995976;