Submissions for variant NM_007194.4(CHEK2):c.1374_1375inv (p.Lys458_Ala459delinsAsnSer)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000233221	SCV000289663	pathogenic	Familial cancer of breast	2024-01-13	criteria provided, single submitter	clinical testing	This variant, c.1374_1375delinsCT, is a complex sequence change that results in the deletion of 2 and insertion of 2 amino acid(s) in the CHEK2 protein (p.Lys458_Ala459delinsAsnSer). RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 240738). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 12, partial intron inclusion, and inclusion of a cryptic exon and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001753705	SCV002005290	uncertain significance	not provided	2023-01-25	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22419737, 19782031)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001775104	SCV002012433	uncertain significance	Predisposition to cancer	2021-10-28	criteria provided, single submitter	clinical testing	The CHEK2 c.1374_1375delinsCT (p.Lys458_Ala459delinsAsnSer) change replaces two nucleotides at position 1374-1375 with two new nucleotides resulting in an in-frame substitution of two amino acids at codons 458 and 459 in exon 12. The affected nucleotides are part of the exon 12 consensus splice site. This change is absent in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). In silico tools that predict the impact of sequence changes on splicing indicate that this change may create or strengthen a splice site (PP3), but this prediction has not been confirmed by RNA studies. A different change at codon 459 that replaces the alanine residue with a proline residue results in skipping of exon 12 (PMID: 33011440). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this change has not been reported in individuals with CHEK2-associated cancers. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, PP3.
Ambry Genetics	RCV002379014	SCV002696385	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	The c.1374_1375delAGinsCT variant (also known as p.K458_A459delinsNS), located in coding exon 11 of the CHEK2 gene, results from an in-frame deletion of AG and insertion of CT at nucleotide positions 1374 to 1375. This results in the deletion of 2 amino acids (KA) and the insertion of 2 amino acids (NS) at codons 458 and 459. However, this change occurs in the final two base pairs of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. RNA studies have shown that the c.1375G>T alteration alone results in a transcript that skips coding exon 11, but the impact was shown to be incomplete (Rofes P et al. J Mol Diagn, 2020 12;22:1453-1468). These nucleotide positions are highly conserved in available vertebrate species. These amino acid positions are well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish this splice donor site. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.