Submissions for variant NM_000051.3(ATM):c.3212A>G (p.Asn1071Ser) (rs755237639)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000274159	SCV000367041	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000274159	SCV000622397	uncertain significance	Ataxia-telangiectasia syndrome	2019-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with serine at codon 1071 of the ATM protein (p.Asn1071Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs755237639, ExAC 0.02%) but has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 302246). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000575982	SCV000672631	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-07	criteria provided, single submitter	clinical testing	Insufficient evidence
Color	RCV000575982	SCV001354070	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-28	criteria provided, single submitter	clinical testing

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