ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.672G>C (p.Lys224Asn) (rs769731317)

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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 RCV000221484 SCV000277470 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-30 criteria provided, single submitter clinical testing Insufficient or inconclusive evidence
Invitae RCV000474412 SCV000546718 uncertain significance Ataxia-telangiectasia syndrome 2019-08-19 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 224 of the ATM protein (p.Lys224Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs769731317, ExAC 0.009%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 233153). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). 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 RCV000485993 SCV000564610 uncertain significance not specified 2014-11-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.672G>C at the cDNA level, p.Lys224Asn (K224N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Lys224Asn 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 Lysine and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. ATM Lys224Asn occurs at a position that is highly conserved in mammals and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether ATM Lys224Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589106 SCV000694331 uncertain significance not provided 2017-02-03 criteria provided, single submitter clinical testing Variant summary: The ATM c.672G>C (p.Lys224Asn) variant involves the alteration of a non-conserved nucleotide. It is located outside of some commonly known domains (InterPro, UniProt). 4/4 in silico tools used predict damaging outcome for this variant. This variant was found in 1/121204 control chromosomes from ExAC at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. It has been reported as germline variant by one laboratory in ClinVar and as somatic variant in one breast and one large intestine carcinoma samples in COSMIC. One internal sample (germline testing) carrying this variant also carries another variant of uncertain significance APC c.730-3C>T. One clinical diagnostic laboratory has classified this variant as uncertain significance. Taken together, this variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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