ClinVar Miner

Submissions for variant NM_002907.4(RECQL):c.132_135del (p.Lys44_Lys45insTer)

dbSNP: rs775055596
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001225633 SCV001397917 uncertain significance not provided 2023-09-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys45*) in the RECQL gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in RECQL cause disease. This variant is present in population databases (rs775055596, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 25915596, 32338768). ClinVar contains an entry for this variant (Variation ID: 953353). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 RCV001225633 SCV001788902 uncertain significance not provided 2023-07-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not an established mechanism of disease; Observed in individuals with breast or prostate cancer, but also in unaffected controls (Cybulski et al., 2015; Nguyen-Dumont et al., 2020; Dorling et al., 2021); Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 32338768, 25915596, 33471991, 33804961)
Ambry Genetics RCV002379859 SCV002694839 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-08 criteria provided, single submitter clinical testing The c.132_135delGAAA variant, located in coding exon 2 of the RECQL gene, results from a deletion of 4 nucleotides at nucleotide positions 132 to 135, causing a translational frameshift with a predicted alternate stop codon (p.K45*). This variant has been identified in a French Canadian high risk breast cancer family (Cybulski C et al. Nat. Genet., 2015 Jun;47:643-6). This variant has also been reported in a patient with non-aggressive prostate cancer (Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). This variant was reported in 4/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, the evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001225633 SCV001552203 likely pathogenic not provided no assertion criteria provided clinical testing The RECQL p.K45* variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs775055596) and in control databases in 9 of 236492 chromosomes (1 female, 8 males) at a frequency of 0.00003806 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 8 of 102454 chromosomes (freq: 0.000078) and African in 1 of 14874 chromosomes (freq: 0.000067), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The c.132_135del variant leads to a premature stop codon at position 45 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the RECQL gene have been suggested in the literature to contribute to breast cancer susceptibility (Banerjee_2015_PMID:26125302; Cybulski_2015_PMID:25915596). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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