rs533184563

Variant names:

• chr17-61847138-G-A
• rs533184563
• NM_032043.3:c.590C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-61847138-G-A
• chr17-61847138-G-C
• chr17-61847138-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_032043.3(BRIP1):​c.590C>T​(p.Ser197Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 2.77

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.590C>T	p.Ser197Phe	missense_variant	Exon 6 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.590C>T	p.Ser197Phe	missense_variant	Exon 6 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251352 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135852

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: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461460 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 727062

Gnomad4 AFR exome AF: 0.00

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: 0.0000513

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74346

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000491

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Aug 11, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, this variant has been reported in an individual with prostate cancer (PMID: 29368341 (2018)), and in several breast cancer cases and healthy controls in a cancer risk association study (PMID: 33471991 (2021)). This variant has also been observed in the homozygous state in an individual with breast cancer (PMID: 26921362 (2016)). The frequency of this variant in the general population, 0.000054 (7/129100 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jan 22, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with breast or prostate cancer and also in unaffected controls (PMID: 26921362, 29368341, 32832836, 33471991); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26921362, 29368341, 32832836, 33471991) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:2

Jan 03, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser197Phe variant in BRIP1 has been reported in 2 European individuals wit h breast cancer, once in the homozygous state and once in the heterozygous state , as well as one heterozygous individual with prostate cancer (Easton 2016, Velh o 2018). This variant has also been identified in 0.008% (2/24964) of African ch romosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Furthermore, although the BRIP1 gene has been reported i n association with multiple cancer types, a ClinGen Expert Panel has only defini tively associated the gene to ovarian cancer and refuted its association with br east cancer. There also appears to be limited evidence for an association with p rostate cancer and no good evidence for an association with colon cancer. In sum mary, the clinical significance of the p.Ser197Phe variant is uncertain. ACMG/AM P Criteria applied: PM2_Supporting. -

Nov 06, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRIP1 c.590C>T (p.Ser197Phe) results in a non-conservative amino acid change located in the ATP-binding domain (IPR014001) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.4e-05 in 268220 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.590C>T has been reported in the literature in individuals affected with breast cancer and prostate cancer (Easton_2016, IsaacssonVelho_2018). Large-scale meta-analyses found that BRIP1 confer high risk for familial ovarian cancer, but not for familial breast cancer (PMID: 29368626, 30733081), therefore, the reported breast cancer patients might not support a pathogenic role for the variant of interest. In addition, one of the reported breast cancer cases was described as homozygous for the variant, however no Fanconi features were noted (Easton_2016). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 3/60466 cases, but was also found in 3/53461 controls (Dorling_2021 through LOVD). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33471991, 26921362, 29368341). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:2

Feb 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S197F variant (also known as c.590C>T), located in coding exon 5 of the BRIP1 gene, results from a C to T substitution at nucleotide position 590. The serine at codon 197 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was observed within individuals with a personal history of breast cancer (Easton DF et al. J Med Genet, 2016 May;53:298-309). This variant was also identified in multiple cohorts of males diagnosed with prostate cancer (Isaacsson Velho P et al. Prostate, 2018 04;78:401-40; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43).This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jul 26, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with phenylalanine at codon 197 of the BRIP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26921362) and prostate cancer (PMID: 29368341). In a large breast cancer case-control study, this variant has been observed in 3/60463 cases and 3/53458 controls; OR=0.884 (95%CI 0.178 to 4.381); p-value=1 (PMID: 33471991 - Leiden Open Variation Database DB-ID BRIP1_000673). This variant has also been identified in 9/282754 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. -

Breast and/or ovarian cancer Uncertain:1

Apr 05, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1

-

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 197 of the BRIP1 protein (p.Ser197Phe). This variant is present in population databases (rs533184563, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 26921362). ClinVar contains an entry for this variant (Variation ID: 142178). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRIP1 protein function with a negative predictive value of 95%. 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. -

BRIP1-related disorder Uncertain:1

Mar 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRIP1 c.590C>T variant is predicted to result in the amino acid substitution p.Ser197Phe. This variant has been reported as having uncertain significance in a patient with recurrent or metastatic adenocarcinoma of the prostate (Table S1, Isaacsson Velho et al. 2018. PubMed ID: 29368341) and has also been reported in a study of breast cancer patients (Tables S1 and S2, Easton et al. 2016. PubMed ID: 26921362); however, the variant has also been described in unaffected controls (Dorling et al. 2021. PubMed ID: 33471991, supplementary data, reported as 59924499_G_A). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142178/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast Uncertain:1

Mar 15, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.65	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	0.055	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.1	N;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.018	D;.
Sift4G	Uncertain	0.059	T;T
Polyphen		1.0	D;.
Vest4		0.39
MVP		0.92
MPC		0.21
ClinPred		0.36	T
GERP RS		4.3
Varity_R		0.089
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: rs533184563; hg19: chr17-59924499;