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. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The ENST00000259008.7(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R419P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: BRIP1 ENST00000259008.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:21 B:6 O:1
• Conservation: PhyloP100: 2.97
• Publications: 24 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: Uncertain_significance. The variant received 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 VariationId is 128153.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000259008.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	NM_032043.3	MANE Select	c.1255C>T	p.Arg419Trp	missense	Exon 9 of 20	NP_114432.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRIP1	ENST00000259008.7	TSL:1 MANE Select	c.1255C>T	p.Arg419Trp	missense	Exon 9 of 20	ENSP00000259008.2
	BRIP1	ENST00000682453.1		c.1255C>T	p.Arg419Trp	missense	Exon 10 of 21	ENSP00000506943.1
	BRIP1	ENST00000683039.1		c.1255C>T	p.Arg419Trp	missense	Exon 10 of 21	ENSP00000508303.1

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

GnomAD2 exomes AF: 0.000358 AC: 90 AN: 251150 AF XY: 0.000413

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 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

African (AFR) AF: 0.0000897 AC: 3 AN: 33460

American (AMR) AF: 0.000134 AC: 6 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.000568 AC: 49 AN: 86240

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000268 AC: 298 AN: 1111652

Other (OTH) AF: 0.000248 AC: 15 AN: 60378

GnomAD4 genome AF: 0.000296 AC: 45 AN: 151954 Hom.: 1 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74232

African (AFR) AF: 0.0000483 AC: 2 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000530 AC: 36 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000371 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	2	Hereditary cancer-predisposing syndrome (6)
-	4	-	Fanconi anemia complementation group J (4)
-	3	1	not provided (4)
-	3	-	Familial cancer of breast (3)
-	1	1	Familial cancer of breast;C1836860:Fanconi anemia complementation group J (2)
-	1	1	not specified (3)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	Breast carcinoma (1)
-	1	-	BRIP1-related disorder (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	1	-	Malignant tumor of breast (1)
-	1	-	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.021	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
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

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