Submissions for variant NM_000051.4(ATM):c.4505G>T (p.Cys1502Phe)

gnomAD frequency: 0.00003  dbSNP: rs759340881

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199907	SCV000254110	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 1502 of the ATM protein (p.Cys1502Phe). 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: 216217). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.
Ambry Genetics	RCV000234909	SCV000276649	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-27	criteria provided, single submitter	clinical testing	The p.C1502F variant (also known as c.4505G>T), located in coding exon 29 of the ATM gene, results from a G to T substitution at nucleotide position 4505. The cysteine at codon 1502 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was identified in 1/1358 non-cancer control individuals in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741) as well as in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med 2018 04;7(4):1349-1358 ). 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.
GeneDx	RCV000589257	SCV000278827	uncertain significance	not provided	2021-05-03	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with breast cancer as well as a control individual in a melanoma case-control study (Decker 2017, Hauke 2018, Engel 2018, Pritchard 2018); This variant is associated with the following publications: (PMID: 29641532, 29514593, 29522266, 28779002)
Color Diagnostics, LLC DBA Color Health	RCV000234909	SCV000292214	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-20	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 1502 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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: 28779002). This variant has been identified in 1/251326 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589257	SCV000694285	uncertain significance	not provided	2016-07-01	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.4505G>T (p.Cys1502Phe) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a "damaging" outcome, although these predictions have yet to be functionally assessed. The variant of interest is not known to be located in a functional domain (UniPort). The variant of interest was observed in the large, broad control population, ExAC, 1/121396, which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/252 for Ataxia-Telangiectasisa or 1/1999 for BrC. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, multiple reputable clinical laboratories cite variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as "variant of uncertain significance," until additional information becomes available.
PreventionGenetics, part of Exact Sciences	RCV004553088	SCV004117961	uncertain significance	ATM-related disorder	2022-11-21	criteria provided, single submitter	clinical testing	The ATM c.4505G>T variant is predicted to result in the amino acid substitution p.Cys1502Phe. This variant has been reported in individuals with breast cancer (Table S5, Decker B et al 2017. PubMed ID: 28779002; Table S2, Hauke et al. 2018. PubMed ID: 29522266) . This variant has also been reported in a control individual in a melanoma case-control study (Table S3, Pritchard AL et al 2018. PubMed ID: 29641532). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108163414-G-T) and is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/216217/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Institute of Immunology and Genetics Kaiserslautern	RCV004771468	SCV005382231	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2024-09-17	criteria provided, single submitter	clinical testing	ACMG Criteria: PM2_P, PP3; Variant was found in heterozygous state.
Natera, Inc.	RCV000199907	SCV001462329	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing