ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.629_632del (p.Ser210fs)

dbSNP: rs756131136
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255001 SCV000322578 likely pathogenic not provided 2017-06-29 criteria provided, single submitter clinical testing This deletion of four nucleotides in CHEK2 is denoted c.629_632delCAGT at the cDNA level and p.Ser210PhefsX6 (S210FfsX6) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CAGT[delCAGT]TTAT. The deletion causes a frameshift which changes a Serine to a Phenylalanine at codon 210, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. CHEK2 c.629_632delCAGT, also known as c.758_761delCAGT (p.Ser253PhefsX6) based on an alternate transcript, has been observed in at least three individuals with a personal and/or family history of breast and/or ovarian cancer (Bernards 2016, Li 2016, Thompson 2016). Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Invitae RCV001070188 SCV001235404 pathogenic Familial cancer of breast 2023-06-24 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: 265588). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26534844, 26786923). This variant is present in population databases (rs756131136, gnomAD 0.001%). This sequence change creates a premature translational stop signal (p.Ser210Phefs*6) 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).
CeGaT Center for Human Genetics Tuebingen RCV000255001 SCV001245714 pathogenic not provided 2020-07-01 criteria provided, single submitter clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital RCV000255001 SCV001450085 likely pathogenic not provided 2020-03-25 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001804992 SCV002052978 pathogenic Hereditary cancer-predisposing syndrome 2021-07-06 criteria provided, single submitter clinical testing This variant deletes 4 nucleotides in exon 5 of the CHEK2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer in the literature (PMID: 26534844, 26786923). This variant has been identified in 1/227036 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CHEK2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics RCV001804992 SCV002657195 pathogenic Hereditary cancer-predisposing syndrome 2022-04-14 criteria provided, single submitter clinical testing The c.629_632delCAGT pathogenic mutation, located in coding exon 4 of the CHEK2 gene, results from a deletion of 4 nucleotides at nucleotide positions 629 to 632, causing a translational frameshift with a predicted alternate stop codon (p.S210Ffs*6). This mutation has been identified in a cohort of women with breast and/or ovarian cancer who also had a strong family history of breast cancer (Li J et al. J. Med. Genet. 2016 Jan;53:34-42). In addition to the clinical data presented in the literature, 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. RCV001070188 SCV004045160 pathogenic Familial cancer of breast 2023-06-26 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics RCV001070188 SCV004217729 pathogenic Familial cancer of breast 2022-08-23 criteria provided, single submitter clinical testing

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