Submissions for variant NM_000051.4(ATM):c.3530G>C (p.Cys1177Ser)

dbSNP: rs587782470

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131572	SCV000186578	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-15	criteria provided, single submitter	clinical testing	The p.C1177S variant (also known as c.3530G>C), located in coding exon 23 of the ATM gene, results from a G to C substitution at nucleotide position 3530. The cysteine at codon 1177 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198090	SCV000254086	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1177 of the ATM protein (p.Cys1177Ser). 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: 142446). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	RCV000485057	SCV000572908	uncertain significance	not provided	2017-01-26	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.3530G>C at the cDNA level, p.Cys1177Ser (C1177S) at the protein level, and results in the change of a Cysteine to a Serine (TGT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Cys1177Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Cys1177Ser occurs at a position that is conserved in mammals and is located in region of interaction with beta-adaptin (Tavtigian 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Cys1177Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000485057	SCV002010825	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467177	SCV004210226	uncertain significance	Familial cancer of breast	2023-06-29	criteria provided, single submitter	clinical testing