RECQL

Inheritance Pattern: AR

Disease ID:MONDO:0957266

Submitter: PanelApp Australia

Inheritance Pattern: Unknown

Disease ID:MONDO:0016248

Submitter: ClinGen

Inheritance Pattern: AD

Disease ID:MONDO:0007254

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0016419

Submitter: ClinGen

RECQL was first reported in relation to hereditary breast cancer in 2015 through two publications (Cybulski et al and Sun et al). RECQL is a DNA helicase and part of a 5 gene family [RECQL1 (RECQL), Bloom syndrome protein (BLM, formerly RECQ2), Werner syndrome helicase (WRN, formerly RECQ3), RECQL4, and RECQL5] associated with rare recessive DNA-repair syndromes such as WRN, Bloom Syndrome and Rothmund-Thomson Syndrome, but thus far RECQL is not associated with a recessive disorder. The proposed mechanism of pathogenicity is through loss of function / truncating or splice/frameshift variants, with missense variants being less commonly implicated. Evidence disputing this gene-disease relationship includes case-control data and experimental data. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there is no disease associated with RECQL in OMIM, and curations to refute or dispute can be split when needed. **Summary of Case-Control Data: 5.5 POINTS** This gene-disease relationship has been studied in at least 4 case-control cohorts at the single variant level and 7 case-control studies at the aggregate variant level. There is limited evidence supporting the gene-disease relationship from small to medium size case-control studies at the aggregate variant level in specific populations, for example in the Han Chinese of northern China (1 point, PMID: 25945795) and African American women (3 points, PMID: 32427313). In addition, Cybulski et al, 2015 (PMID:25915596) showed a significant association of aggregated pathogenic RECQL variants with breast cancer (0.5 point). The same paper also reported the association of a truncating variant (p.Arg215*) and a splice variant (c.1667_1667+3delAGTAA) with breast cancer (0.5 point for each variant). However, at least two studies published in 2017 and 2020 focusing on the single splice variant c.1667_1667+3delAGTA showed no significant association of this splice variant with breast cancer (PMID:27832498, 32824581). In addition, in 2021 two large case-control studies [CARRIERS (PMID: 33471974) and BCAC (PMID: 33471991); both with more than 32 thousand cases and controls] did not identify a significant association of aggregate loss of function (LOF) variants in RECQL and breast cancer. Another case-control study at the aggregate variant level with smaller size of Australian women with breast cancer reports no association of LOF RECQL variants with breast cancer (PMID: 30224651). These studies provide evidence to refute the association. **Summary of Experimental Data : 1.75 POINTS** An experimental study reported the role of RECQL as a DNA helicase and in the DNA repair process (0.5 point, PMID: 15899892). In addition, another study showed that RECQL is expressed in the breast cancer cell line MDA-MB-231, and silencing of RECQL alters expression of (CCNB1, CD55, and FST - upregulated) and 6 down regulated genes (CDK6, CENPA, EBNA1BP2, PTK2, SSR1, and TGFBI) (0.25 point, PMID:25483193). RECQL and FOXA1 (FOXA1 is a transcription factor for Estrogen Receptor 1 (ESR1) and mutations in FOXA1 are associated with estrogen positive breast cancer) co immunoprecipitate (0.5 point, PMID: 33468559). Sharma S, et al., 2005 (PMID: 18074021) showed cancer cells display defective DNA repair and damage responses (0.5 point), as do the MEF cells from RECQL knock-out mice (0.5 point). Notably, many experiments referenced above do not replicate a heterozygous loss of function state and instead eliminate or reduce expression of both alleles (i.e. siRNA or knock-out mice). **Overall Summary:** In summary, given the lack of significant association in the large breast cancer case/control studies to date, the relationship between RECQL and autosomal dominant hereditary breast cancer has been disputed, regardless of minor points assigned for some supporting data. More evidence is needed to either support or entirely refute the role of RECQL in hereditary breast cancer. This gene-disease pair was originally evaluated as moderate by the Breast/Ovarian Cancer GCEP on 9/28/2016. This re-curation was approved by the ClinGen Hereditary Diseases GCEP on 2/17/2023 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0957266

Submitter: Labcorp Genetics (formerly Invitae)