Submissions for variant NM_000051.4(ATM):c.1855A>C (p.Asn619His)

gnomAD frequency: 0.00002  dbSNP: rs140882609

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131223	SCV000186175	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	The p.N619H variant (also known as c.1855A>C), located in coding exon 11 of the ATM gene, results from an A to C substitution at nucleotide position 1855. The asparagine at codon 619 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in the germline of 1 of 8,920 ethnically matched normal population control subjects and in 0 of 516 samples from a study of chronic lymphocytic leukemia patients of European descent (Tiao G et al. Leukemia, 2017 Oct;31:2244-2247). This variant was reported in 2/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved through mammals. 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.
Invitae	RCV000203692	SCV000260170	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 619 of the ATM protein (p.Asn619His). This variant is present in population databases (rs140882609, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 142224). 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 histidine 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.
GeneDx	RCV000587634	SCV000278811	uncertain significance	not provided	2023-05-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26123645)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001530924	SCV000694201	uncertain significance	not specified	2023-01-23	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1855A>C (p.Asn619His) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250960 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1855A>C has been previously reported in one uterine serous carcinoma sample without confirmation of its origin (germline vs somatic) (Jones_2015) and a Chronic Lymphocytic Leukemia patient (Tiao_2017). In a case-control study focusing on individuals with pancreatic cancer, the variant was identified in one case and one healthy control (Yu_2021). These reports do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) have cited the variant, with 5 submitters classifying the variant as uncertain significance and one submitter classifying it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000131223	SCV000902882	likely benign	Hereditary cancer-predisposing syndrome	2016-06-29	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131223	SCV002533453	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003407554	SCV004115946	uncertain significance	ATM-related condition	2022-12-29	criteria provided, single submitter	clinical testing	The ATM c.1855A>C variant is predicted to result in the amino acid substitution p.Asn619His. This variant has been reported as a variant of unknown significance in a uterine serous carcinoma sample (Table S3, Jones et al. 2015. PubMed ID: 26123645). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108123596-A-C) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142224/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003467169	SCV004209481	uncertain significance	Familial cancer of breast	2023-09-09	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131223	SCV004228108	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000203692	SCV002076178	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-20	no assertion criteria provided	clinical testing