Submissions for variant NM_007194.4(CHEK2):c.478A>G (p.Ile160Val)

gnomAD frequency: 0.00002  dbSNP: rs876659950

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221570	SCV000276929	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	The p.I160V variant (also known as c.478A>G), located in coding exon 3 of the CHEK2 gene, results from an A to G substitution at nucleotide position 478. The isoleucine at codon 160 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in an individual diagnosed with breast cancer (Megid TBC et al. Front Oncol, 2022 Aug;12:873395). This alteration has also been identified in an individual diagnosed with renal cell cancer (Yngvadottir B et al. Hum Mol Genet, 2022 Aug;31:3001-3011). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459190	SCV000550461	uncertain significance	Familial cancer of breast	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 160 of the CHEK2 protein (p.Ile160Val). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 36003761). ClinVar contains an entry for this variant (Variation ID: 232725). 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 tolerated. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589153	SCV000698805	uncertain significance	not provided	2017-02-16	criteria provided, single submitter	clinical testing	Variant summary: The CHEK2 c.478A>G (p.Ile160Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent from 121352 control chromosomes. In addition, a clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000221570	SCV000906523	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-18	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 160 of the CHEK2 protein. 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 individuals affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000071, 36003761; Color internal data) and in an individual affected with familial breast and thyroid cancer (PMID: 32443704). One of the individuals affected with breast cancer also carried a pathogenic variant in the BRCA2 gene that could explain the observed phenotype (PMID: 36003761). This variant has been identified in 3/282814 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.
Mendelics	RCV000459190	SCV001141369	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001788089	SCV002030149	uncertain significance	Li-Fraumeni syndrome 2	2021-07-27	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].