rs150624408

Variant names:

• chr17-61799185-G-A
• rs150624408
• NM_032043.3:c.1255C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-61799185-G-A
• chr17-61799185-G-C
• chr17-61799185-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3 BP6

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:21 B:6 O:1
• Conservation: PhyloP100: 2.97

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.

• 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
BRIP1	NM_032043.3	c.1255C>T	p.Arg419Trp	missense_variant	Exon 9 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.1255C>T	p.Arg419Trp	missense_variant	Exon 9 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 151954 Hom.: 1 Cov.: 32

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

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

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

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:21 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 08, 2022	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	Nov 17, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 05, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Aug 18, 2022	- -

Fanconi anemia complementation group J Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 12, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 03, 2020	- -

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2025	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) -
Uncertain significance, 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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BRIP1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 10, 2024	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. -

Familial cancer of breast Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 03, 2023	Criteria applied: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 20, 2022	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. -
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. -

not specified Uncertain:1 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 24, 2025	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 23, 2023

- -

BRIP1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 03, 2024

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

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 12, 2016

- -

Breast carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 05, 2014

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Feb 15, 2024

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

Other links and lift over

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