Submissions for variant NM_007194.4(CHEK2):c.860del (p.Lys287fs)

dbSNP: rs886039731

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255418	SCV000322682	likely pathogenic	not provided	2016-08-17	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in CHEK2 is denoted c.860delA at the cDNA level and p.Lys287ArgfsX17 (K287RfsX17) at the protein level. The normal sequence, with the base that is deleted in braces, is ATCA[A]GATT. The deletion causes a frameshift which changes a Lysine to an Arginine at codon 287, and creates a premature stop codon at position 17 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Counsyl	RCV000409327	SCV000489377	likely pathogenic	Familial cancer of breast	2016-09-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409327	SCV000633224	pathogenic	Familial cancer of breast	2024-06-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys287Argfs*17) in the CHEK2 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). 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: 265686). Studies have shown that this premature translational stop signal results in skipping of exon 8 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260330	SCV001437262	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-09-29	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.860delA (p.Lys287ArgfsX17) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 225074 control chromosomes (gnomAD). c.860delA has been reported in the literature to be found in a cohort of women with ovarian cancer (Arvai_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic (1x) / likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002446501	SCV002677844	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	The c.860delA pathogenic mutation, located in coding exon 7 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 860, causing a translational frameshift with a predicted alternate stop codon (p.K287Rfs*17). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV000409327	SCV004020163	pathogenic	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.