Submissions for variant NM_002907.4(RECQL):c.468T>G (p.Ile156Met)

gnomAD frequency: 0.00013  dbSNP: rs777214281

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV003492143	SCV000838647	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001230378	SCV001402854	uncertain significance	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 156 of the RECQL protein (p.Ile156Met). This variant is present in population databases (rs777214281, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 29341116, 30224651, 35264596). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 584818). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RECQL protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001230378	SCV001759676	uncertain significance	not provided	2024-04-11	criteria provided, single submitter	clinical testing	Observed in individuals with breast or ovarian cancer and incompletely segregates with disease in at least one family (PMID: 30224651, 29341116, 35264596); In silico analysis indicates that this missense variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868); This variant is associated with the following publications: (PMID: 30610487, 30224648, 32517021, 35264596, 30224651, 19151156, 27248010, 29341116, 33471991)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001230378	SCV002049699	uncertain significance	not provided	2021-08-26	criteria provided, single submitter	clinical testing	The RECQL c.468T>G; p.Ile156Met variant (rs777214281) is reported in the literature in multiple individuals and families affected with breast cancer (Tervasmaki 2018). This variant was found to be significantly enriched among Finnish breast cancer patients compared to controls; however, it was also absent from several affected members of two families (Tervasmaki 2018). This variant is found in the Finnish European population with an overall allele frequency of 0.06% (15/24676 alleles) in the Genome Aggregation Database. The isoleucine at codon 156 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.273). Due to limited and conflicting information, the clinical significance of the p.Ile156Met variant is uncertain at this time. References: Tervasmaki et al. Rare missense mutations in RECQL and POLG associate with inherited predisposition to breast cancer. Int J Cancer. 2018 Jun 1;142(11):2286-2292. PMID 29341116.
Ambry Genetics	RCV004026773	SCV002637814	uncertain significance	not specified	2023-02-20	criteria provided, single submitter	clinical testing	The p.I156M variant (also known as c.468T>G), located in coding exon 4 of the RECQL gene, results from a T to G substitution at nucleotide position 468. The isoleucine at codon 156 is replaced by methionine, an amino acid with highly similar properties. This variant was reported in 2/4536 female BRCA1/2-negative index patients diagnosed with breast or ovarian cancer and was not observed in 4576 cancer-free control subjects above 40 years of age (Li N et al. Nat Genet, 2018 10;50:1346-1348). This alteration was also identified in 6/1946 Finnish breast cancer cases and 0/1408 Finnish controls (Tervasmäki A et al. Int J Cancer, 2018 06;142:2286-2292). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001230378	SCV004220227	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00061 (15/24676 chromosomes in European (Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 29341116 (2018), 30224651 (2018), 35264596 (2022)) as well as in unaffected controls (PMID: 35264596 (2022)). It has been reported in individuals with breast cancer as well as in unaffected controls in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RECQL)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Revvity Omics, Revvity	RCV003492144	SCV004236562	uncertain significance	RECON progeroid syndrome	2019-05-10	criteria provided, single submitter	clinical testing