ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6652A>C (p.Ser2218Arg) (rs749261367)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575940 SCV000660474 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-14 criteria provided, single submitter clinical testing The c.6652A>C variant (also known as p.S2218R), located in coding exon 45 of the ATM gene, results from an A to C substitution at nucleotide position 6652. The serine at codon 2218 is replaced by arginine, an amino acid with dissimilar properties. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to strengthen an alternate splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing and produces an out of frame transcript in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000575940 SCV000904712 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-18 criteria provided, single submitter clinical testing This missense variant replaces serine with arginine at codon 2218 of the ATM 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. Splice site prediction tools suggest that this variant may strengthen a cryptic splice acceptor site. However, this prediction has not been confirmed in published RNA studies. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 3/251178 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.
Invitae RCV000815731 SCV000956200 uncertain significance Ataxia-telangiectasia syndrome 2019-05-02 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 2218 of the ATM protein (p.Ser2218Arg). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs749261367, ExAC 0.006%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 478930). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV001420803 SCV001623175 uncertain significance not specified 2021-04-16 criteria provided, single submitter clinical testing Variant summary: ATM c.6652A>C (p.Ser2218Arg) results in a non-conservative amino acid change located in the FAT domain (IPR003151) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251178 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6652A>C has been reported in the literature in individuals affected with colorectal cancer (CRC) or breast cancer (Yurgelun_2017, Lu_2015, Edvardsen_2007). These reports however, do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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