Submissions for variant NM_000051.4(ATM):c.2561C>A (p.Ser854Tyr)

gnomAD frequency: 0.00003  dbSNP: rs778123895

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478056	SCV000569205	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD)
Ambry Genetics	RCV000574598	SCV000665675	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-22	criteria provided, single submitter	clinical testing	The p.S854Y variant (also known as c.2561C>A), located in coding exon 16 of the ATM gene, results from a C to A substitution at nucleotide position 2561. The serine at codon 854 is replaced by tyrosine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	RCV000706877	SCV000835951	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 854 of the ATM protein (p.Ser854Tyr). This variant is present in population databases (rs778123895, gnomAD 0.006%). 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: 420385). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Color Diagnostics, LLC DBA Color Health	RCV000574598	SCV000911593	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with tyrosine at codon 854 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has been identified in 2/251426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000574598	SCV002532301	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-23	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387855	SCV004099582	uncertain significance	not specified	2023-09-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470560	SCV004207028	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing