chr17-61801429-G-A

Variant names:

• chr17-61801429-G-A
• rs587778139
• NM_032043.3:c.964C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_032043.3(BRIP1):​c.964C>T​(p.Gln322*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,502 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q322Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRIP1 NM_032043.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 6.09
• Publications: 1 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-61801429-G-A is Pathogenic according to our data. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-61801429-G-A is described in CliVar as Pathogenic. Clinvar id is 133763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.964C>T	p.Gln322*	stop_gained	Exon 8 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.964C>T	p.Gln322*	stop_gained	Exon 8 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727048

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111774

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Oct 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln322*) in the BRIP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRIP1 are known to be pathogenic (PMID: 16116423, 17033622, 21964575). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 133763). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Familial cancer of breast Pathogenic:1

Jun 01, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.1
Vest4		0.89
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.49		Position offset: 45

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

Other links and lift over

dbSNP: rs587778139; hg19: chr17-59878790;