ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8293G>A (p.Gly2765Ser) (rs748634900)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165932 SCV000216688 pathogenic Hereditary cancer-predisposing syndrome 2018-07-03 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000200060 SCV000253672 likely pathogenic Ataxia-telangiectasia syndrome 2019-07-15 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 2765 of the ATM protein (p.Gly2765Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs748634900, ExAC 0.001%). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 21792198) and breast cancer (PMID: 10534763, 19781682). ClinVar contains an entry for this variant (Variation ID: 186351). Experimental studies have shown that this missense change causes the loss of ATM kinase activity and a cell-cycle checkpoint defect in cells from affected individuals (PMID: 19431188, 21792198). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000200060 SCV000694377 likely pathogenic Ataxia-telangiectasia syndrome 2017-04-06 criteria provided, single submitter clinical testing Variant summary: The ATM c.8293G>A (p.Gly2765Ser) variant involves the alteration of a conserved nucleotide located in the Protein kinase-like domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121582 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). The variant has been reported in Ataxia Telangectasia (A-T) patients as well as breast cancer patients, however segregation studies in a breast cancer family showed the variant to be absent in an affected grandmother, while the variant was present in two unaffected siblings (age at testing was not specified). This data indicate a lack of co-segregation of this variant with breast cancer in this family (Izatt_1999), although the effect of a limited penetrance, cannot be ruled out. Furthermore, a sample tested at our laboratory also carries another pathogenic BRCA2 c.5946delT. Among the cohort of patients clinically diagnosed with A-T, this variant was seen in compound heterozygosity with other possibly pathogenic variants. Well controlled functional studies have shown the variant to lead to loss of ATM Kinase activity, while retaining almost complete ATM protein expression (Barone_2009, Reiman_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. In summary, while this variants association with breast cancer cannot be firmly established, the fact that it results in complete loss of ATM Kinase activity, along with its presence in A-T patients suggests that the variant to be Likely Pathogenic for a phenotype of Ataxia Telangectasia.

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