NM_032043.3:c.2543G>A

Variant names:

• chr17-61693462-C-T
• rs374334794
• NM_032043.3:c.2543G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM5 PP3_Strong PP5

The NM_032043.3(BRIP1):​c.2543G>A​(p.Arg848His) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R848S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:5
• Conservation: PhyloP100: 5.05
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• familial ovarian cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• Fanconi anemia complementation group J

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG, LIMITED, NO_KNOWN Submitted by: ClinGen, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-61693463-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142529.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 17-61693462-C-T is Pathogenic according to our data. Variant chr17-61693462-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141499.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.2543G>A	p.Arg848His	missense_variant	Exon 18 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.2543G>A	p.Arg848His	missense_variant	Exon 18 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152072 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461436 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727038

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111682

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74272

African (AFR) AF: 0.0000724 AC: 3 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast;C1836860:Fanconi anemia complementation group J Pathogenic:2 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 848 of the BRIP1 protein (p.Arg848His). This variant is present in population databases (rs374334794, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, Fanconi anemia, melanoma, and/or ovarian cancer (PMID: 26790966, 27074266, 29368626, 31558676, 33028645). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 141499). 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 expected to disrupt BRIP1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRIP1 function (PMID: 33028645). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Strong+PS4_Supporting+PM3_Supporting -

Fanconi anemia complementation group J Pathogenic:2

Aug 13, 2020

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 04, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRIP1 c.2543G>A (p.Arg848His) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251348 control chromosomes. c.2543G>A has been reported in the literature in homozygous state in individuals affected with Fanconi Anemia Complementation Group J (Kamal_2020, Steinberg-Shemer_2020). It has also been reported in heterozygous state in individuals affected with cutaneous malignant melanoms (Tuominen_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in increased chromosomal breakage after exposure to increasing concentrations of mitomycin C in peripheral blood lymphocytes of an affected individual and loss of helicase activity of the mutant protein in an in vitro assay (Kamal_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33028645, 315588676, 27074266). ClinVar contains an entry for this variant (Variation ID: 141499). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 24, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R848H variant (also known as c.2543G>A), located in coding exon 17 of the BRIP1 gene, results from a G to A substitution at nucleotide position 2543. The arginine at codon 848 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in a woman with bilateral breast cancer and ovarian cancer who had a family history of breast cancer and leukemia (Kim H et al. Cancer Res Treat 2016 Jan). This alteration was also seen in a Swedish melanoma family and segregated with disease in three individuals (Tuominen R et al. Genes Chromosomes Cancer. 2016 Jul;55(7):601-11). This variant has also been reported in the homozygous state in multiple individuals diagnosed with Fanconi anemia (Steinberg-Shemer O et al. Haematologica, 2020 07;105:1825-1834, Kamal L et al. Cold Spring Harb Mol Case Stud, 2020 10;6:). In vitro functional studies showed that this variant has deficient helicase activity, however, the physiological relevance of this finding is unclear (Kamal L et al. Cold Spring Harb Mol Case Stud, 2020 10;6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jun 09, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 848 of the BRIP1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A function study has reported that this variant lacks helicase activity in vitro (PMID: 33028645). This variant has been observed in at least seven individuals affected with breast and/or ovarian cancer (PMID: 26790966, 27074266, 29368626, 33471991; Leiden Open Variation Database DB-ID BRIP1_000121; Color internal data). In one of the individual affected with ovarian cancer, the proband and other carrier family members were also affected with cutaneous malignant melanoma, squamous cell carcinoma of the skin and liver cancer (PMID: 27074266). This variant also has been reported in at least two homozygous carriers diagnosed with Fanconi anemia (PMID: 31558676, 33028645). In one Fanconi anemia case, the carrier lymphocytes were confirmed to exhibit chromosomal breakage after mitomycin C treatment (PMID: 33028645). This variant also has been reported in unaffected individuals in cancer case-control studies (PMID: 31214711, 32980694, 33471991; Leiden Open Variation Database DB-ID BRIP1_000121). This variant has been identified in 1/31386 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Uncertain:2

Aug 19, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with breast cancer or ovarian cancer and in a family with multiple cases of melanoma (Kim 2016, Tuominen 2016, Weber-Lassalle 2018); This variant is associated with the following publications: (PMID: 31558676, 29368626, 27074266, 26709662, 26790966) -

Aug 13, 2019

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -

Neurodevelopmental delay Pathogenic:1

-

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Sep 09, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

According to the ACMG SVI adaptation criteria we chose these criteria: PS3 (strong pathogenic): Kamal et al. (2020) PMID:33028645, PM2 (supporting pathogenic): gnomAD 4.1.0: 0,0006% gnomAD 3.1 (non-cancer): 0, PM3 (medium pathogenic): homozygous in 2 individuals with FA by Kamal (2020), PMID: 33028645 (in one FA case, the carrier lymphocytes were confirmed to exhibit chromosomal breakage after mitomycin C treatment) + homozygous in 1 individual with FA by Steinberg-Shemer (2020), PMID: 31558676, PP3 (supporting pathogenic): REVEL: 0.93 -

Ovarian cancer;C1836860:Fanconi anemia complementation group J Uncertain:1

Apr 26, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Familial cancer of breast Uncertain:1

Jul 31, 2023

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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H
PhyloP100		5.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.6	D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.86
MVP		1.0
MPC		0.75
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.87
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.30		Position offset: -32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs374334794; hg19: chr17-59770823;