ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1052A>C (p.Glu351Ala)

gnomAD frequency: 0.00001  dbSNP: rs786202893
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165950 SCV000216706 uncertain significance Hereditary cancer-predisposing syndrome 2022-04-05 criteria provided, single submitter clinical testing The p.E351A variant (also known as c.1052A>C), located in coding exon 9 of the CHEK2 gene, results from an A to C substitution at nucleotide position 1052. The glutamic acid at codon 351 is replaced by alanine, an amino acid with dissimilar properties. This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). 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.
Invitae RCV000474853 SCV000550437 uncertain significance Familial cancer of breast 2023-12-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 351 of the CHEK2 protein (p.Glu351Ala). This variant is present in population databases (rs786202893, gnomAD 0.0009%). 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: 186366). 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.
Color Diagnostics, LLC DBA Color Health RCV000165950 SCV001351701 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-17 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with alanine at codon 351 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251292 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV002291581 SCV002584658 uncertain significance Predisposition to cancer 2022-07-07 criteria provided, single submitter clinical testing The CHEK2 c.1052A>C (p.Glu351Ala) missense change has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with breast cancer (PMID: 25186627). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics RCV000474853 SCV004217510 uncertain significance Familial cancer of breast 2023-10-14 criteria provided, single submitter clinical testing

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