Submissions for variant NM_000051.4(ATM):c.8264A>C (p.Tyr2755Ser)

dbSNP: rs1591199410

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001027336	SCV001189877	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-11	criteria provided, single submitter	clinical testing	The p.Y2755S variant (also known as c.8264A>C), located in coding exon 55 of the ATM gene, results from an A to C substitution at nucleotide position 8264. The tyrosine at codon 2755 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243992	SCV001417184	uncertain significance	Ataxia-telangiectasia syndrome	2023-09-14	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 2755 of the ATM protein (p.Tyr2755Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 806732). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ATM function (PMID: 36029002). 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	RCV004689948	SCV005184800	uncertain significance	not specified	2024-05-13	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8264A>C (p.Tyr2755Ser) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250688 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8264A>C has been reported in the literature in individuals affected with chronic lymphocytic leukemia (e.g., Navrkalova_2016, Petrackova_2022), although whether the variant was of germline or somatic origin was unclear. The variant was also identified in individuals undergoing genetic testing for hereditary cancer, including at least one individual with no history of cancer (e.g., Slavin_2019). These reports do not provide unequivocal conclusions about association of the variant with ATM-related disorders. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g., Petrackova_2022). The following publications have been ascertained in the context of this evaluation (PMID: 27479817, 36029002, 31056428). ClinVar contains an entry for this variant (Variation ID: 806732). Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect - Invitae Patient Insights Network	RCV001535475	SCV001749404	not provided	Ataxia-telangiectasia syndrome; Malignant tumor of breast		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-20-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.