Submissions for variant NM_007194.4(CHEK2):c.1254del (p.Phe418fs)

dbSNP: rs587780173

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115991	SCV000149900	likely pathogenic	not provided	2016-08-29	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted CHEK2 c.1254delT at the cDNA level and p.Phe418LeufsX19 (F418LfsX19) at the protein level. The normal sequence, with the base that is deleted in braces, is CTTTT[T]ATCT. The deletion causes a frameshift, which changes a Phenylalanine to a Leucine at codon 418, and creates a premature stop codon at position 19 of the new reading frame. This variant was observed in at least one individual with breast cancer (Susswein 2015), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be likely pathogenic.
Invitae	RCV000635839	SCV000757264	pathogenic	Familial cancer of breast	2023-07-29	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 128052). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312, 29520813). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe418Leufs*19) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400).
Ambry Genetics	RCV002415594	SCV002681659	pathogenic	Hereditary cancer-predisposing syndrome	2019-06-27	criteria provided, single submitter	clinical testing	The c.1254delT pathogenic mutation, located in coding exon 10 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1254, causing a translational frameshift with a predicted alternate stop codon (p.F418Lfs*19). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel in a patient with breast cancer (Susswein LR et al. Genet. Med., 2016 08;18:823-32). This alteration has also been reported in two individuals with prostate cancer (Wu Y et al. Prostate, 2018 06;78:607-615). 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.	RCV000635839	SCV004043776	pathogenic	Familial cancer of breast	2023-06-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.