Submissions for variant NM_000051.4(ATM):c.93G>C (p.Lys31Asn)

dbSNP: rs863224583

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197073	SCV000254163	uncertain significance	Ataxia-telangiectasia syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 31 of the ATM protein (p.Lys31Asn). 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: 216237). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000564628	SCV000672706	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-01	criteria provided, single submitter	clinical testing	The p.K31N variant (also known as c.93G>C), located in coding exon 2 of the ATM gene, results from a G to C substitution at nucleotide position 93. The lysine at codon 31 is replaced by asparagine, an amino acid with similar properties. This amino acid position is highly conserved in through mammals, but not in available lower 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.
Color Diagnostics, LLC DBA Color Health	RCV000564628	SCV000687883	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-14	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 31 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 hereditary cancer in the literature. This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192366	SCV001360420	uncertain significance	not specified	2019-07-26	criteria provided, single submitter	clinical testing	Variant summary: ATM c.93G>C (p.Lys31Asn) results in a non-conservative amino acid change located in the telomere-length maintenance and DNA damage repair (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251158 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.93G>C in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000564628	SCV004014945	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV003319332	SCV004023828	uncertain significance	not provided	2023-02-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV004567420	SCV005056980	uncertain significance	Familial cancer of breast	2024-02-16	criteria provided, single submitter	clinical testing