rs4988347

chr17-61847144-A-Gchr17-61847144-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032043.3(BRIP1):c.584T>C(p.Leu195Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,613,712 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L195F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (6 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24 O:1
• Conservation: PhyloP100: 0.364

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004298687).
• BP6: Variant 17-61847144-A-G is Benign according to our data. Variant chr17-61847144-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61847144-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.584T>C	p.Leu195Pro	missense_variant	6/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.584T>C	p.Leu195Pro	missense_variant	6/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00923

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00194 AC: 487 AN: 251340 Hom.: 2 AF XY: 0.00200 AC XY: 271 AN XY: 135838

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00911

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00228 AC: 3328 AN: 1461406 Hom.: 6 Cov.: 31 AF XY: 0.00219 AC XY: 1589 AN XY: 727042

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00800

Gnomad4 NFE exome AF: 0.00242

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74478

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00923

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00155 Hom.: 2

Bravo AF: 0.00120

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00160 AC: 194

Asia WGS AF: 0.000289 AC: 1 AN: 3474

EpiCase AF: 0.00202

EpiControl AF: 0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:24 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 08, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	BRIP1: BP4 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRIP1 p.Leu195Pro variant was identified in 21 of 13772 proband chromosomes (frequency: 0.002) from individuals or families with prostate cancer, breast cancer, ovarian cancer, and Lynch syndrome and was present in 19 of 21561 control chromosomes (frequency: 0.0009) from healthy individuals (Bodian 2014, Kote-Jarai 2009, Kuusisto 2011, Lewis 2005, Rafnar 2011, Ramus 2015, Ray 2009, Rutter 2003, Seal 2006, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs4988347) as "With Likely benign allele", ClinVar (4x benign, 3x likely benign), Clinvitae, and the Zhejiang Colon Cancer Database (6x, likely neutral). The variant was not identified in Cosmic or the MutDB database. The variant was identified in control databases in 537 of 277082 chromosomes (2 homozygous) at a frequency of 0.002 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 8 of 24028 chromosomes (freq: 0.0003), Other in 10 of 6464 chromosomes (freq: 0.002), Latino in 24 of 34414 chromosomes (freq: 0.0007), European in 255 of 126622 chromosomes (freq: 0.002), Finnish in 226 of 25772 chromosomes (freq: 0.009), and South Asian in 14 of 30782 chromosomes (freq: 0.0005). The variant was not observed in the Ashkenazi Jewish or East Asian populations. A study by Lewis 2005 utilizing in silico bioinformatic tools predicted this variant may affect mRNA folding and exonic splicing enhancers. However, the same study showed that the variant did not segregate with disease in a family with breast cancer (Lewis 2005). The p.Leu195 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. -

not specified Benign:4 Other:1

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	GeneDx	Dec 21, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 01, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 11, 2021	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 23, 2022	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 08, 2017	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. -

Fanconi anemia complementation group J Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 05, 2016	- -
Benign, 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 29, 2019	- -

Familial cancer of breast Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

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

Mar 03, 2023

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

BRIP1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2020

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

Neoplasm of ovary Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Jul 05, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	5.2
Dann	Benign	0.23
DEOGEN2	Benign	0.067	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.75	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.10	N;.
REVEL	Benign	0.10
Sift	Benign	0.32	T;.
Sift4G	Benign	0.39	T;T
Polyphen		0.0	B;.
Vest4		0.13
MVP		0.41
MPC		0.26
ClinPred		0.0012	T
GERP RS		-0.011
Varity_R		0.032
gMVP		0.47

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: rs4988347; hg19: chr17-59924505; COSMIC: COSV99034601;