Submissions for variant NM_000051.4(ATM):c.3978C>A (p.Asn1326Lys)

gnomAD frequency: 0.00002  dbSNP: rs778123057

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165616	SCV000216352	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	The p.N1326K variant (also known as c.3978C>A), located in coding exon 25 of the ATM gene, results from a C to A substitution at nucleotide position 3978. The asparagine at codon 1326 is replaced by lysine, an amino acid with similar properties. In a study of 196 women with breast cancer and 185 unaffected controls from Cameroon and Uganda, this variant was observed in one breast cancer patient from Cameroon (Adedokun B et al. Cancer Epidemiol Biomarkers Prev. 2020 02;29:359-367). This variant was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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	RCV000472893	SCV000547036	uncertain significance	Ataxia-telangiectasia syndrome	2022-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1326 of the ATM protein (p.Asn1326Lys). This variant is present in population databases (rs778123057, gnomAD 0.01%). 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: 186087). 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. 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	RCV000481947	SCV000566255	uncertain significance	not provided	2021-04-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual undergoing hereditary cancer panel testing (Adedokun 2020); This variant is associated with the following publications: (PMID: 31871109)
PreventionGenetics, part of Exact Sciences	RCV000481947	SCV000805545	uncertain significance	not provided	2017-06-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000472893	SCV000838530	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165616	SCV002536684	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002478509	SCV002780807	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-10-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114316	SCV003800864	uncertain significance	not specified	2023-01-23	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3978C>A (p.Asn1326Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251102 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3978C>A has been reported in the literature in individuals affected with breast cancer. This report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted 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.
Baylor Genetics	RCV003468748	SCV004210075	uncertain significance	Familial cancer of breast	2023-08-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165616	SCV004360798	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 1326 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 been reported in an individual affected with breast cancer (PMID: 31871109). This variant has been identified in 3/282486 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.
Natera, Inc.	RCV000472893	SCV002081570	uncertain significance	Ataxia-telangiectasia syndrome	2020-10-29	no assertion criteria provided	clinical testing