Submissions for variant NM_007194.4(CHEK2):c.1022A>C (p.Asn341Thr)

gnomAD frequency: 0.00003  dbSNP: rs773846607

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000467334	SCV000550508	uncertain significance	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 341 of the CHEK2 protein (p.Asn341Thr). This variant is present in population databases (rs773846607, gnomAD 0.008%). 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: 410044). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV000480457	SCV000564875	uncertain significance	not provided	2023-05-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15095295, 32546565, 19782031, 22419737)
Ambry Genetics	RCV000575429	SCV000666345	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	The p.N341T variant (also known as c.1022A>C), located in coding exon 9 of the CHEK2 gene, results from an A to C substitution at nucleotide position 1022. The asparagine at codon 341 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was not seen in 516 female index patients at increased risk for hereditary breast cancer but was seen in 1/500 healthy control women over 50 years old (Dufault MR et al. Int. J. Cancer. 2004 Jun;110(3):320-5). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This alteration was also identified in an individual diagnosed with ovarian cancer (Song H et al. J Med Genet, 2021 May;58:305-313). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000575429	SCV000684546	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-11	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with threonine at codon 341 of the CHEK2 protein. This variant is also known as NM_001005735.1:c.1151A>C (p.Asn384Thr) in the literature. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual each affected with ovarian and lung cancer (PMID: 28843361, 32546565) and also in an unaffected control from a breast/ovarian cancer case-control study (PMID: 15095295). This variant has been identified in 6/282562 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000575429	SCV002537015	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-12	criteria provided, single submitter	curation
Baylor Genetics	RCV000467334	SCV004217533	uncertain significance	Familial cancer of breast	2023-09-28	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000480457	SCV001963527	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000480457	SCV001968547	uncertain significance	not provided		no assertion criteria provided	clinical testing