rs779741278

Variant names:

• chr17-61683805-C-CA
• rs779741278
• NM_032043.3:c.3240dupT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_032043.3(BRIP1):​c.3240dupT​(p.Ala1081CysfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D1080D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:4
• Conservation: PhyloP100: -0.437

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

Our verdict: Uncertain_significance. The variant received 5 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. There are 14 pathogenic variants in the truncated region.
• PP5: Variant 17-61683805-C-CA is Pathogenic according to our data. Variant chr17-61683805-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 324348.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRIP1	NM_032043.3	c.3240dupT	p.Ala1081CysfsTer5	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.3240dupT	p.Ala1081CysfsTer5	frameshift_variant	Exon 20 of 20	1	NM_032043.3	ENSP00000259008.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152166 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: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251228 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26134

Gnomad4 EAS exome AF: 0.000176 AC: 7 AN: 39696

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1112002

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000192 AC: 0.000192382 AN: 0.000192382

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000586 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Apr 06, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 20 of the BRIP1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. The truncated protein is expected to disrupt the TopBP1 binding domain (a.a. 1106-1178) and an acetylation site (p.Lys1249) in the C-terminus, 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 affected with sarcoma, prostate cancer, and bilateral breast cancer (PMID: 27498913, 31214711, 32566746). This variant has been identified in 1/251228 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRIP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3240dupT variant, located in coding exon 19 of the BRIP1 gene, results from a duplication of T at nucleotide position 3240, causing a translational frameshift with a predicted alternate stop codon (p.A1081Cfs*5). This stop codon occurs near the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and removes the last 165 amino acids of the protein. The exact functional impact of these removed amino acids is unknown. This alteration was detected in a patient diagnosed with bilateral breast cancer at age 47, her mother, who was diagnosed with breast cancer at age 70, and a maternal aunt, who was diagnosed with breast cancer at ages 58 and 70 (Kaneyasu T et al. NPJ Breast Cancer. 2020 Jun;6:25). This alteration has also been detected in a cohort of 549 Japanese men with prostate cancer (Kimura H et al. Br J Cancer, 2022 Nov;127:1680-1690). 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. -

Familial cancer of breast Pathogenic:1 Uncertain:1

Feb 27, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

May 30, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2

Jan 11, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This duplication of one nucleotide in BRIP1 is denoted c.3240dupT at the cDNA level and p.Ala1081CysfsX5 (A1081CfsX5) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TTGA[dupT]GCCA. The duplication causes a frameshift which changes an Alanine to a Cysteine at codon 1081, and creates a premature stop codon at position 5 of the new reading frame. Due to the position of the variant, nonsense mediated decay is not expected to occur, but the variant might cause loss of normal protein function through protein truncation.?? The disrupted region at the end of the gene is not located in a known functional domain. This variant has been reported in at least one individual with sarcoma, who also carried BRIP1 Glu767Asp (Ballinger 2016). Based on currently available evidence, it is unclear whether this duplication is a pathogenic variant or a benign variant. We consider it to be a variant of uncertain significance. -

Aug 13, 2019

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa. -

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

Feb 02, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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

Dec 07, 2024

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.Ala1081Cysfs*5) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 169 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs779741278, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with sarcoma and prostate cancer (PMID: 27498913, 31214711). ClinVar contains an entry for this variant (Variation ID: 324348). 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. -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Malignant tumor of breast Pathogenic:1

Aug 31, 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.3240dupT (p.Ala1081CysfsX5, in last exon) results in a premature termination codon, predicted to cause a truncation of the encoded protein and is not prone to nonsense mediated decay. The variant allele was found at a frequency of 6.1e-05 in 313543 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than estimated for a pathogenic variant in BRIP1 causing Breast Cancer (6.1e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.3240dupT has been reported in the literature in individuals affected with Breast Cancer, Prostate Cancer and Gastric cancer (Kaneyasu_2020, Momozawa_2020, Suzuki_2020, Akamatsu_2022) as well as in controls (Momozawa_2020, Okawa_2023). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=5), likely pathogenic (n=4) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

May 01, 2019

Cancer Genomics Group, Japanese Foundation For Cancer Research

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=48/152	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs779741278; hg19: chr17-59761166;