Submissions for variant NM_000051.4(ATM):c.3899A>G (p.Tyr1300Cys)

gnomAD frequency: 0.00001  dbSNP: rs183263185

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212005	SCV000209731	uncertain significance	not provided	2024-07-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33309985, 33471991, Bapat2022[Somatic], 30287823, 29641532, 36243179)
Ambry Genetics	RCV000159719	SCV000216595	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-07	criteria provided, single submitter	clinical testing	The p.Y1300C variant (also known as c.3899A>G), located in coding exon 25 of the ATM gene, results from an A to G substitution at nucleotide position 3899. The tyrosine at codon 1300 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in 0/7051 unselected breast cancer patients and 1/11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). In another study, this alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, 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 variant has also been identified in 0/12503 unselected Japanese colorectal cancer patients and in 2/23705 controls . (Fujita M et al. Clin Gastroenterol Hepatol, 2020 Dec). 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. Based on the available evidence, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV000398586	SCV000367049	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000398586	SCV000546823	likely benign	Ataxia-telangiectasia syndrome	2024-01-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159719	SCV000687506	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 1300 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 identified in two individuals affected with breast cancer (Color Health internal data). In a large case-control study including participants with Japanese ancestry, this variant was reported in 0/7051 of women with breast cancer and 1/11241 of women without breast cancer (OR=0, CI=0.0-62.1), 0/53 of men with breast cancer and 1/12490 of men without breast cancer (OR=0, CI=0.0-8036.8)(PMID: 30287823). In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 3/53461 controls (OR=0.295, 95%CI 0.031 to 2.833, p-value=0.347; PMID: 33471991). This variant has been identified in 16/251266 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.
Counsyl	RCV000398586	SCV000791970	uncertain significance	Ataxia-telangiectasia syndrome	2017-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281973	SCV002570613	uncertain significance	not specified	2022-07-21	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3899A>G (p.Tyr1300Cys) 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 6e-05 in 298672 control chromosomes (gnomAD, Fujita_2020). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (6e-05 vs 0.001), allowing no conclusion about variant significance. c.3899A>G has been reported in the literature in at-least one individual affected with Breast Cancer, colorectal cancer, or unaffected controls (examples: Momozawa_2018, Fujita_2020, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
MGZ Medical Genetics Center	RCV002288672	SCV002581606	uncertain significance	Familial cancer of breast	2022-08-01	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002288672	SCV003843001	uncertain significance	Familial cancer of breast	2023-01-19	criteria provided, single submitter	clinical testing	The ATM c.3899A>G (p.Tyr1300Cys) missense change has a maximum subpopulation frequency of 0.039% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. In case-control studies, this variant has been reported in 0 of 7051 breast cancer patients and 1 of 11241 female controls (PMID: 30287823), in 0 of 12053 colorectal cancer cases and 2 of 23705 controls (PMID: 33309985), and in 0 of 57 patients with cutaneous melanoma and at least two other primary cancers and 1 of 1358 non-cancer control individuals (PMID: 29641532). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002288672	SCV003936023	uncertain significance	Familial cancer of breast	2023-06-06	criteria provided, single submitter	clinical testing	a variant of uncertain significance in the ATM gene (p.Tyr1300Cys). This sequence change replaces tyrosine with cysteine at codon 1300 of the ATM protein (p.Tyr1300Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs183263185, ExAC 0.05%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 181952) with 6 submissions all of which describe it as of uncertain significance, two stars, no conflicts. In-silico predictions show benign computational verdict based on 11 benign predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor, PrimateAI and SIFT vs 1 pathogenic prediction from MutationTaster. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Therefore, it has been classified as a Variant of Uncertain Significance. Pathogenic/likely pathogenic mutations in the ATM gene increases susceptibility to breast cancer (OMIM # 114480).
Baylor Genetics	RCV002288672	SCV004212034	uncertain significance	Familial cancer of breast	2023-04-02	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000398586	SCV002081492	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-17	no assertion criteria provided	clinical testing