rs150624408

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6

The NM_032043.3(BRIP1):​c.1255C>T​(p.Arg419Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000268 in 1,613,364 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R419R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

BRIP1
NM_032043.3 missense

Scores

4
13
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:21B:6O:1

Conservation

PhyloP100: 2.97
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.75
BP6
Variant 17-61799185-G-A is Benign according to our data. Variant chr17-61799185-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128153.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=18, Likely_benign=6, not_provided=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRIP1NM_032043.3 linkc.1255C>T p.Arg419Trp missense_variant Exon 9 of 20 ENST00000259008.7 NP_114432.2 Q9BX63-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRIP1ENST00000259008.7 linkc.1255C>T p.Arg419Trp missense_variant Exon 9 of 20 1 NM_032043.3 ENSP00000259008.2 Q9BX63-1

Frequencies

GnomAD3 genomes
AF:
0.000296
AC:
45
AN:
151954
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000289
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00125
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000530
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000358
AC:
90
AN:
251150
Hom.:
1
AF XY:
0.000413
AC XY:
56
AN XY:
135718
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.000397
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000588
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000484
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000265
AC:
387
AN:
1461410
Hom.:
1
Cov.:
32
AF XY:
0.000301
AC XY:
219
AN XY:
727034
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.000230
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000568
Gnomad4 FIN exome
AF:
0.000168
Gnomad4 NFE exome
AF:
0.000268
Gnomad4 OTH exome
AF:
0.000248
GnomAD4 genome
AF:
0.000296
AC:
45
AN:
151954
Hom.:
1
Cov.:
32
AF XY:
0.000310
AC XY:
23
AN XY:
74232
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000289
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00125
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000530
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000365
Hom.:
1
Bravo
AF:
0.000208
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000395
AC:
48
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000546
EpiControl
AF:
0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:21Benign:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:4Benign:2
Aug 01, 2018
GeneKor MSA
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 20, 2018
True Health Diagnostics
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 05, 2022
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Feb 08, 2022
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Aug 18, 2022
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 17, 2020
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Fanconi anemia complementation group J Uncertain:4
Jul 02, 2018
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 28, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Dec 03, 2020
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 12, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:3Benign:1
Feb 04, 2025
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ovarian, breast, prostate, melanoma, pancreatic, colorectal, and other cancers (PMID: 19935797, 26315354, 26921362, 28135145, 29368626, 30651582, 30414346, 32659497, 34326862, 35534704, 33850299); This variant is associated with the following publications: (PMID: 27150160, 29368626, 19935797, 12872252, 24728327, 26315354, 28135145, 26921362, 23555315, 28767289, 30414346, 31159747, 30651582, 32659497, 32283892, 33471991, 35467778, 34284872, 32658311, 29641532, 34326862, 35534704, 33850299) -

Apr 10, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The BRIP1 c.1255C>T (p.Arg419Trp) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 34284872 (2022), 26315354 (2019)), prostate cancer (PMIDs: 35467778 (2022), 19935797 (2009)), melanoma (PMID: 30414346 (2019)), and colorectal cancer (PMID: 32283892 (2020)), as well as in reportedly healthy individuals (PMIDs: 32658311 (2021), 26315354 (2019)). In one large breast cancer association study, this variant was seen more frequently in reportedly healthy individuals than individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRIP1)). The frequency of this variant in the general population, 0.0007 (23/33052 chromosomes in Other non-Finnish European 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 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. -

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

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BRIP1: BS2 -

Familial cancer of breast Uncertain:3
Jul 03, 2023
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PP3 -

Jun 20, 2022
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The BRIP1 c.1255C>T (p.Arg419Trp) missense change has a maximum subpopulation frequency of 0.059% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with ovarian and breast cancer, melanoma, colorectal cancer, hereditary prostate cancer and sporadic pancreatic ductal adenocarcinoma (PMID: 19935797, 26315354, 28135145, 28767289, 29368626, 30414346, 31206626, 32283892, 32659497). To our knowledge, this variant has not been reported in the literature in individuals with Fanconi anemia. In addition, this variant was observed in unaffected controls (PMID: 29368626), and in five individuals reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the role of this variant in disease. It has therefore been classified as of uncertain significance. -

Mar 02, 2023
Myriad Genetics, Inc.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not specified Uncertain:1Benign:1Other:1
Feb 24, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: BRIP1 c.1255C>T (p.Arg419Trp) results in a non-conservative amino acid change located in the Helicase-like, DEXD box c2 type (IPR006554) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 277550 control chromosomes, predominantly at a frequency of 0.00059 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 9.44 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRIP1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05). c.1255C>T has been reported in the literature in individuals affected with Breast and Ovarian Cancer, Pancreatic Cancer, Melanoma, Prostate Cancer, and Colorectal Cancer and in unaffected controls (e.g. Ray_2009, Haiman_2013, Ramus_2015, Easton_2016, Yurgelun_2017, Shindo_2017, Potjer_2018, Lassalle_2018, Schubert_2019, Krivokuca_2019, Wang_2019, Dorling_2021, Brady_2022, Krivokuca_2022). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported at our laboratory (CHEK2 c.1100delC [p.Thr367fs], ClinVar: 128042) and in the literature (BRCA1 c.5266dup, [p.Gln1756fs], ClinVar: 17677; Krivokuca_2022), providing supporting evidence for a benign role. 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: 32658311, 24728327, 35467778, 33471991, 26921362, 23555315, 34284872, 30651582, 30414346, 26315354, 19935797, 12872252, 30426508, 28767289, 31159747, 30982232, 29368626, 28135145). ClinVar contains an entry for this variant (Variation ID: 128153). Based on the evidence outlined above, the variant was classified as likely benign. -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Uncertain:1Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Uncertain:1
May 23, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

BRIP1-related disorder Uncertain:1
Jan 03, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The BRIP1 c.1255C>T variant is predicted to result in the amino acid substitution p.Arg419Trp. This variant has been observed in individuals with breast, prostate, ovarian, colorectal and pancreatic cancer, as well as in healthy control individuals (Rutter et al. 2003. PubMed ID: 12872252; Ray et al. 2009. PubMed ID: 19935797; Table S1, Bodian et al. 2014. PubMed ID: 24728327 Ramus et al. 2015. PubMed ID: 26315354; Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/128153/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Malignant tumor of breast Uncertain:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The BRIP1 p.Arg419Trp variant was identified in 6 of 6936 proband chromosomes (frequency: 0.001) from individuals or families with prostate or ovarian cancer and was present in 2 of 8336 control chromosomes (frequency: 0.0002) from healthy individuals (Bodian 2014, Ramus 2015, Ray 2009). The variant was also identified in dbSNP (ID: rs150624408) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, Color Genomics, GeneDx, and 4 clinical laboratories), Clinvitae, MutDB, and the Zhejiang University Database. The variant was not identified in the Cosmic database. The variant was identified in control databases in 95 of 276856 chromosomes (1 homozygous) at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: include African in 3 of 24020 chromosomes (freq: 0.0001), “Other” in 6 of 6460 chromosomes (freq: 0.001), Latino in 5 of 34350 chromosomes (freq: 0.0001), European in 56 of 126446 chromosomes (freq: 0.0004), Ashkenazi Jewish in 4 of 10148 chromosomes (freq: 0.0004), East Asian in 2 of 18866 chromosomes (freq: 0.0001), Finnish in 1 of 25786 chromosomes (freq: 0.00004), and South Asian in 18 of 30780 chromosomes (freq: 0.001). The p.Arg419 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. This variant is classified as a variant of uncertain significance. -

Ovarian neoplasm Uncertain:1
Aug 12, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast carcinoma Uncertain:1
Dec 05, 2014
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1
Feb 15, 2024
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

According to the ACMG SVI adaptation criteria we chose these criteria: BS1 (supporting benign): 84x het in gnomAD non Cancer, in V4 432X, BS2 (strong benign): 1x homzygous in gnomAD nonCancer, in v4 2X -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.46
T;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Uncertain
0.21
D
MutationAssessor
Uncertain
2.8
M;M
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-4.3
D;.
REVEL
Uncertain
0.60
Sift
Uncertain
0.010
D;.
Sift4G
Uncertain
0.021
D;D
Polyphen
1.0
D;.
Vest4
0.81
MVP
0.95
MPC
0.69
ClinPred
0.14
T
GERP RS
3.5
Varity_R
0.63
gMVP
0.76

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs150624408; hg19: chr17-59876546; COSMIC: COSV52005960; API