ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3886C>T (p.Pro1296Ser) (rs864622654)

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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 RCV000573505 SCV000668148 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000573505 SCV000682168 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
Counsyl RCV000206762 SCV000788637 uncertain significance Ataxia-telangiectasia syndrome 2017-05-02 criteria provided, single submitter clinical testing
GeneDx RCV000478981 SCV000568020 uncertain significance not provided 2015-09-22 criteria provided, single submitter clinical testing This variant is denoted ATM c.3886C>T at the cDNA level, p.Pro1296Ser (P1296S) at the protein level, and results in the change of a Proline to a Serine (CCT>TCT). This variant has been reported in at least one individual with Ataxia-telangiectasia (A-T) (Soukupova 2014). ATM Pro1296Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Pro1296Ser occurs at a position that is conserved across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether ATM Pro1296Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000206762 SCV000261594 uncertain significance Ataxia-telangiectasia syndrome 2017-09-21 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1296 of the ATM protein (p.Pro1296Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to co-occur with an ATM frameshift variant, c.1563_1564delAG (p.Glu522Ilefs*42), in an individual affected with ataxia-telangiectasia (PMID: 21833744). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 220775). 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 disruptive, 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.

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