rs730881645

chr17-61683849-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_032043.3(BRIP1):c.3196del(p.Ser1066HisfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S1066S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRIP1 NM_032043.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.19

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 12 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 18 pathogenic variants in the truncated region.
• PP5: Variant 17-61683849-GA-G is Pathogenic according to our data. Variant chr17-61683849-GA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRIP1	NM_032043.3	c.3196del	p.Ser1066HisfsTer12	frameshift_variant	20/20	ENST00000259008.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRIP1	ENST00000259008.7	c.3196del	p.Ser1066HisfsTer12	frameshift_variant	20/20	1	NM_032043.3	P2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

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: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251422 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135882

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461846 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727228

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74354

Gnomad4 AFR AF: 0.000169

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 26, 2023	This variant deletes 1 nucleotide in exon 20 of the BRIP1 gene, creating a frameshift and a 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. This mutant protein would lack the region (codons 1130-1153) that has been shown to be important for TopBP1 binding in vitro and DNA replication-stress response in ex vivo cell culture (PMID: 20159562, 21127055). This variant has been reported in individuals of African ancestry affected with breast cancer (PMID: 25186627, 30130155, 30728895) and in an individual with endometrial cancer (PMID: 26689913, 28452373) in the literature, as well as in additional affected individuals tested by external laboratories (ClinVar variation ID: 182367). This variant has also been identified in 7/282816 chromosomes (7/24958 African chromosomes) in the general population by the Genome Aggregation Database (gnomAD) and in individuals lacking personal history of cancer (Color internal data; FLOSSIES, https://whi.color.com/). Based on the suspected deleterious impact on protein function and observations in affected individuals, this variant is classified as Likely Pathogenic. The occurrence of this variant in the general population (gnomAD) and in some unaffected individuals suggest this variant may show reduced penetrance compared to other pathogenic variants in the BRIP1 gene. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 15, 2023	The c.3196delT variant, located in coding exon 19 of the BRIP1 gene, results from a deletion of one nucleotide at position 3196, causing a translational frameshift with a predicted alternate stop codon (p.S1066Hfs*12). Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of BRIP1, is not expected to trigger nonsense-mediated mRNA decay, and removes the last 173 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the C-terminal region of the protein has been shown by structural, biochemical, and mutational analysis to be relevant for the protein function (Leung CC et al. J. Biol. Chem. 2011 Feb; 286(6):4292-301. Xie J et al. PLoS Genet. 2012 Jul; 8(7):e1002786; Gong Z et al. Mol. Cell. 2010 Feb;37:438-46). In addition, this alteration was identified in multiple studies in patients diagnosed with breast cancer younger than 50 years of age (Tung N et al. Cancer. 2015 Jan;121(1):25-33; Slavin TP et al. Oncotarget. 2019 Jan;10(4):417-423; George SHL et al. JAMA Netw Open, 2021 Mar;4:e210307). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change creates a premature translational stop signal (p.Ser1066Hisfs*12) in the BRIP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 184 amino acid(s) of the BRIP1 protein. This variant is present in population databases (rs730881645, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with breast cancer, lung cancer (PMID: 25186627, 26689913, 30130155, 30728895, 33646313). ClinVar contains an entry for this variant (Variation ID: 182367). This truncation affects the TopBP1-binding region (residues 1130-1153) of the BRIP1 protein. It is expected to disrupt the TopBP1-BRIP1 interaction that plays a critical role on RPA chromatin loading following DNA replication stress and the subsequent activation of the replication checkpoint in response to DNA damage (PMID: 20159562, 21127055). 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 28, 2023

Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 184 amino acids are lost and replaced with11 incorrect amino acids; Observed in individuals with breast and other cancers (Tung et al., 2015; Huang et al., 2018; Zheng et al., 2018; Slavin et al., 2019; George et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29625052, 25186627, 29922827, 30728895, 20159562, 21127055, 30130155, 33646313, 26689913, 34949788, 36451132, 35969835) -

Neoplasm of ovary;C1836860:Fanconi anemia complementation group J Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 01, 2017

- -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 18, 2023

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 29, 2021

Variant summary: BRIP1 c.3196delT (p.Ser1066HisfsX12) results in a premature termination codon in the last exon of the encoded mRNA, therefore it is not expected to result in nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein. No truncations downstream of this position were classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.5e-05 in 282816 control chromosomes, exclusively observed within the African or African-American subpopulation, at a frequency of 0.00028 (i.e. 7/24958 alleles) in the gnomAD database. In addition, this variant has also been reported in 1/2559 African American woman who was older than age 70 and cancer free (in the FLOSSIES database). c.3196delT has been reported in the literature in individuals of African ancestry, who were affected with breast cancer (example, Tung_2014, Zheng_2018, Slavin_2019). However, large-scale meta-analyses found that although BRIP1 mutations may confer risk for familial ovarian cancer, but not associated with increased risk for familial breast cancer (Weber-Lassale_2018, Suszynska_2018); therefore these reports do not allow any conclusions about variant significance. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.213-11T>G). Co-occurring pathogenic variants in different genes have been reported in cancer cases, thus this is not considered to weight as evidence supporting a benign impact of this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported for this variant. Though this truncation does not affect any known domains, in vitro studies have implicated a functional role for the region downstream of this variant in RPA phosphorylation in response to replication stress (i.e. following treatment with some DNA damaging agents) (example, Gong_2010, Xie_2012), however the contribution of these functional effects to the disease pathology remains uncertain. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and four of them classified the variant as likely pathogenic, while one reports a VUS classification. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on reports of its presence in patients with breast cancer (example, Zheng_2018, Slavin_2019), until additional clinical and functional evidence becomes available, the variant was classified as likely pathogenic. -

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: rs730881645; hg19: chr17-59761210;