rs778664039

Variant names:

• chr17-61683652-AATAG-A
• rs778664039
• NM_032043.3:c.3390_3393delCTAT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_032043.3(BRIP1):​c.3390_3393delCTAT​(p.Tyr1131LeufsTer18) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000149 in 1,613,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 4.24

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.096 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PP5: Variant 17-61683652-AATAG-A is Pathogenic according to our data. Variant chr17-61683652-AATAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 229712.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.3390_3393delCTAT	p.Tyr1131LeufsTer18	frameshift_variant	Exon 20 of 20	ENST00000259008.7	NP_114432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRIP1	ENST00000259008.7	c.3390_3393delCTAT	p.Tyr1131LeufsTer18	frameshift_variant	Exon 20 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 250266 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135470

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460812 Hom.: 0 AF XY: 0.0000124 AC XY: 9 AN XY: 726744

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74480

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr1131Leufs*18) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 119 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs778664039, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with prostate cancer or breast cancer (PMID: 27701467, 38348036). This variant is also known as p.I1130fs. ClinVar contains an entry for this variant (Variation ID: 229712). This variant disrupts the TopBP1-binding region of the BRIP1 protein, which plays a critical role in RPA chromatin loading and the activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). While functional studies have not been performed to directly test the effect of this variant on BRIP1 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

May 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Jan 17, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 nucleotides in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein with the last 119 amino acids of the protein replaced with 17 novel amino acids. The truncation is expected to disrupt the TopBP1 binding region and an acetylation site in the C-terminus of the BRIP1 protein, which have been reported to play an important role in DNA replication-stress response and maintaining genomic stability (PMID: 20159562, 21127055, 22792074). This variant has been reported in individuals with early-onset breast cancer (Color internal data) and in an individual affected with prostate cancer (PMID: 27701467). This variant has been identified in 9/250266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the exact mechanism by which this variant causes disease is yet to be determined, the available evidence indicates that this variant is likely to disrupt normal BRIP1 protein function. Therefore, this variant is classified as Likely Pathogenic. -

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3390_3393delCTAT variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of 4 nucleotides at positions 3390 to 3393, causing a translational frameshift with a predicted alternate stop codon (p.Y1131Lfs*18). This alteration occurs at the 3' terminus of theBRIP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 119 amino acids of the protein. The exact functional effect of this alteration is unknown. While the C-terminal region of the BRIP1 protein has been shown by structural, biochemical, and mutational analysis to be relevant for some aspects of BRIP1 protein function (Gong Z et al. Mol. Cell, 2010 Feb;37:438-46; Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301; Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786), functional studies have shown that truncations in the 3' terminus of BRIP1 display normal function in response to intra-strand cross-linking agents (Calvo JA et al. Mol Cancer Res, 2021 Jun;19:1015-1025). In addition, 3' truncations in BRIP1 occurring upstream of this variant have been detected in the homozygous or compound heterozygous state in individuals with no reported features of BRIP1-related Fanconi Anemia (FA-J) (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear. -

Ovarian cancer Pathogenic:1

Aug 26, 2022

BRCAlab, Lund University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ovarian neoplasm;C1836860:Fanconi anemia complementation group J Pathogenic:1

Nov 28, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group J Pathogenic:1

Jul 10, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRIP1 c.3390_3393delCTAT (p.Tyr1131LeufsX18), located in the last exon, results in a premature termination codon, predicted to cause a truncation of the encoded protein. Truncations downstream of this position have not been classified as pathogenic by our laboratory but have been observed in individuals with breast and/or ovarian cancer and early-onset Prostate cancer as reported in the HGMD database. The variant allele was found at a frequency of 3.6e-05 in 250266 control chromosomes. To our knowledge, c.3390_3393delCTAT has not been reported in the literature in individuals affected with Fanconi Anemia Complementation Group J. However, c.3390_3393delCTAT has been reported in the literature in individuals affected with a variety of cancers such as Prostate (example, Hayano_2016); Breast (example, Li_2018, Vasmatzis_2020) and Pancreatic Cancer (example, Emelyanova_2022). Among these ascertained occurrences, it was reported in the germline DNA of an individual with Breast cancer (example Li_2018); as a putative germline variant due to its finding in the normal tissue of a an individual with Pancreatic Cancer (Emelyanova_2022); in settings of comprehensive genomic profiling on a liver biopsy along with other variation such as biallelic inactivation of TP53, CDH1, FOXA1, NIN and other structural rearrangements in which therapies targeting this specific mutation were invalidated over other validated therapies (Vasmatzis_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Complementation Group J. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported however another residue within this region (Threonine 1133) has been reported to be functionally relevant to BRIP1 function. The following publications have been ascertained in the context of this evaluation (PMID: 35309086, 27701467, 30385609, 31685261, 29368626). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Likely pathogenic, n=5; VUS, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic for BRIP1 associated cancer predisposition but its association with a phenotype of autosomal recessive Fanconi Anemia Complementation Group J remains uncertain. -

not provided Pathogenic:1

Nov 11, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 119 amino acids are replaced with 17 different amino acids, and other similar variants have been reported in HGMD; Observed in individuals with breast, prostate or pancreatic cancer (PMID: 27701467, 30385609, 35309086); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22980975, 27701467, 29368626, 31685261, 30254378, 20159562, 21127055, 29420467, 29922827, 35309086, 30385609) -

Familial cancer of breast Pathogenic:1

Mar 19, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs778664039; hg19: chr17-59761013;