Submissions for variant NM_000051.4(ATM):c.4420C>G (p.His1474Asp)

gnomAD frequency: 0.00001  dbSNP: rs587779840

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212016	SCV000149105	uncertain significance	not provided	2023-09-20	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; Observed in individuals with breast, pancreatic, or prostate cancer (PMID: 33436325, 26976419, 28726808); This variant is associated with the following publications: (PMID: 25480502, 33436325, 26976419, 28726808, 33471991, 27479817, 33875564)
Ambry Genetics	RCV000115196	SCV000214609	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	The p.H1474D variant (also known as c.4420C>G), located in coding exon 28 of the ATM gene, results from a C to G substitution at nucleotide position 4420. The histidine at codon 1474 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported as a variant of unknown significance in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test as well as 1/302 individuals with pancreatic cancer (Tung N et al. J Clin Oncol, 2016 May;34:1460-8; Chaffee KG et al. Genet Med, 2018 01;20:119-127). In another study, this alteration was reported in 3/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med, 2021 02;384:428-439). This variant was also reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000206587	SCV000259589	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-27	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 1474 of the ATM protein (p.His1474Asp). This variant is present in population databases (rs587779840, gnomAD 0.002%). This missense change has been observed in individual(s) with breast and prostate cancer (PMID: 26976419, 33436325). ClinVar contains an entry for this variant (Variation ID: 127391). 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 disruptive. 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	RCV000115196	SCV000903206	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with aspartic acid at codon 1474 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. 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: 26976419) and in an individual affected with chronic lymphocytic leukemia (PMID: 27479817). In an international breast cancer case-control meta-analysis, this variant was detected in 3/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/250390 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	RCV000115196	SCV002534734	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-24	criteria provided, single submitter	curation
Athena Diagnostics	RCV000212016	SCV002771847	uncertain significance	not provided	2022-05-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212016	SCV004133257	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	ATM: PM2
Baylor Genetics	RCV003460804	SCV004206333	uncertain significance	Familial cancer of breast	2024-02-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492459	SCV004240713	uncertain significance	Breast and/or ovarian cancer	2022-08-26	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212016	SCV001739763	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000212016	SCV001926326	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212016	SCV001959088	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000206587	SCV002082470	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-27	no assertion criteria provided	clinical testing