NM_032043.3:c.2450A>G

Variant names:

• chr17-61715993-T-C
• rs1555580828
• NM_032043.3:c.2450A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_032043.3(BRIP1):​c.2450A>G​(p.Tyr817Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,866 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y817H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRIP1 NM_032043.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.45
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 43 uncertain in NM_032043.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

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.2450A>G	p.Tyr817Cys	missense	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.2450A>G	p.Tyr817Cys	missense	Exon 17 of 20	ENSP00000259008.2	Q9BX63-1
	BRIP1	ENST00000682453.1		c.2450A>G	p.Tyr817Cys	missense	Exon 18 of 21	ENSP00000506943.1	Q9BX63-1
	BRIP1	ENST00000683039.1		c.2450A>G	p.Tyr817Cys	missense	Exon 18 of 21	ENSP00000508303.1	Q9BX63-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456866 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724560

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 85214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1109248

Other (OTH) AF: 0.00 AC: 0 AN: 60122

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial cancer of breast (1)
-	1	-	Familial cancer of breast;C1836860:Fanconi anemia complementation group J (1)
-	1	-	Ovarian cancer;C1836860:Fanconi anemia complementation group J (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		7.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.56		Gain of loop (P = 0.0166)
MVP		1.0
MPC		0.77
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.89
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1555580828; hg19: chr17-59793354;