rs137852986

Variant names:

• chr17-61716051-G-A
• rs137852986
• NM_032043.3:c.2392C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-61716051-G-A
• chr17-61716051-G-C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_032043.3(BRIP1):​c.2392C>T​(p.Arg798*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,592,634 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000699691: Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated defective ATP hydrolysis and the loss of helicase activity (e.g. London_2008, Barthelemy_2016).; SCV000292128: A functional study has shown that the mutant transcript undergoes nonsense-mediated decay (PMID:26921362).; SCV000600905: The variant was associated with decreased protein expression in experimental studies (PMID:16153896 (2005)).; SCV001550349: Analysis of the variant protein, from lymphoblastoid cell lines, by immunoblotting showed an absence of the protein in both homozygous and heterozygous carriers and absence of homologous recombination (Levran 2005, Litman 2005).". Synonymous variant affecting the same amino acid position (i.e. R798R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: BRIP1 NM_032043.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:47 O:2
• Conservation: PhyloP100: 3.47
• Publications: 84 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: Illumina, Orphanet
• Fanconi anemia complementation group J

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

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000699691: Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated defective ATP hydrolysis and the loss of helicase activity (e.g. London_2008, Barthelemy_2016).; SCV000292128: A functional study has shown that the mutant transcript undergoes nonsense-mediated decay (PMID: 26921362).; SCV000600905: The variant was associated with decreased protein expression in experimental studies (PMID: 16153896 (2005)).; SCV001550349: Analysis of the variant protein, from lymphoblastoid cell lines, by immunoblotting showed an absence of the protein in both homozygous and heterozygous carriers and absence of homologous recombination (Levran 2005, Litman 2005).
• PP5: Variant 17-61716051-G-A is Pathogenic according to our data. Variant chr17-61716051-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032043.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	NM_032043.3	MANE Select	c.2392C>T	p.Arg798*	stop_gained	Exon 17 of 20	NP_114432.2	Q9BX63-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	ENST00000259008.7	TSL:1 MANE Select	c.2392C>T	p.Arg798*	stop_gained	Exon 17 of 20	ENSP00000259008.2	Q9BX63-1
	BRIP1	ENST00000682453.1		c.2392C>T	p.Arg798*	stop_gained	Exon 18 of 21	ENSP00000506943.1	Q9BX63-1
	BRIP1	ENST00000683039.1		c.2392C>T	p.Arg798*	stop_gained	Exon 18 of 21	ENSP00000508303.1	Q9BX63-1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151992 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000166 AC: 41 AN: 247008 AF XY: 0.000187

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.0000885

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000295

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000301 AC: 433 AN: 1440642 Hom.: 0 Cov.: 29 AF XY: 0.000309 AC XY: 221 AN XY: 716002

African (AFR) AF: 0.0000903 AC: 3 AN: 33232

American (AMR) AF: 0.0000905 AC: 4 AN: 44202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25786

East Asian (EAS) AF: 0.00 AC: 0 AN: 39098

South Asian (SAS) AF: 0.0000369 AC: 3 AN: 81324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.000357 AC: 392 AN: 1099290

Other (OTH) AF: 0.000521 AC: 31 AN: 59458

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151992 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74220

African (AFR) AF: 0.000121 AC: 5 AN: 41386

American (AMR) AF: 0.000262 AC: 4 AN: 15266

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.000321

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000148 AC: 18

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Fanconi anemia complementation group J (12)
6	-	-	Familial cancer of breast (6)
6	-	-	Hereditary cancer-predisposing syndrome (6)
6	-	-	not provided (6)
4	-	-	BRIP1-related disorder (4)
3	-	-	Familial cancer of breast;C1836860:Fanconi anemia complementation group J (3)
2	-	-	Ovarian cancer (2)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Breast cancer, early-onset (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1 (1)
1	-	-	Esophageal atresia/tracheoesophageal fistula;C0346153:Familial cancer of breast;C1836860:Fanconi anemia complementation group J (1)
1	-	-	Fanconi anemia (1)
1	-	-	Gastric cancer (1)
1	-	-	Inherited ovarian cancer (without breast cancer) (1)
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		3.5
Vest4		0.87
GERP RS		3.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137852986; hg19: chr17-59793412; COSMIC: COSV51996261;