Submissions for variant NM_000051.4(ATM):c.2275A>G (p.Ser759Gly)

gnomAD frequency: 0.00006  dbSNP: rs148705269

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589762	SCV000149060	uncertain significance	not provided	2023-03-02	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; Observed in individuals with a personal or family history of breast, pancreatic, or other cancers (Goldgar et al., 2011; Lu et al., 2015; Tung et al., 2016; Caminsky et al., 2016; Chaffee et al., 2018; Lerner-Ellis et al., 2021); This variant is associated with the following publications: (PMID: 21787400, 25186627, 26976419, 26898890, 28726808, 31422574, 26689913, 32885271, 34994613)
Ambry Genetics	RCV000115151	SCV000183888	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	The p.S759G variant (also known as c.2275A>G), located in coding exon 14 of the ATM gene, results from an A to G substitution at nucleotide position 2275. The serine at codon 759 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in multiple breast and/or ovarian cancer cohorts, including in an individual with ovarian cancer and a BRCA1 pathogenic variant (Tung N et al. J Clin Oncol, 2016 May;34:1460-8; Caminsky NG et al. Hum Mutat, 2016 07;37:640-52; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration was also reported in 1/302 individuals with both a personal and family history of pancreatic cancer (Chaffee KG et al. Genet Med, 2018 01;20:119-127). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000205470	SCV000259588	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 759 of the ATM protein (p.Ser759Gly). This variant is present in population databases (rs148705269, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, chronic lymphocytic leukemia, low grade glioma, ovarian cancer, pancreatic cancer, and/or uterine cancer (PMID: 26689913, 26898890, 26976419, 28726808, 34326862, 36315919). ClinVar contains an entry for this variant (Variation ID: 127346). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Illumina Laboratory Services, Illumina	RCV000205470	SCV000367035	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-12	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.
Fulgent Genetics, Fulgent Genetics	RCV000515206	SCV000611350	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115151	SCV000682046	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 759 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 26689913, 26898890, 26976419), pancreatic cancer (PMID: 28726808), and chronic lymphocytic leukemia (PMID: 28652578). This variant has been identified in 9/282588 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	RCV002469010	SCV000694214	uncertain significance	not specified	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2275A>G (p.Ser759Gly) 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 3.2e-05 in 251174 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2275A>G has been reported in the literature in individuals affected with Breast Cancer without strong evidence for causality (example: Caminsky_2016, Tung-2016). 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. Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publications have been ascertained in the context of this evaluation (PMID: 21787400, 25186627, 26689913, 26898890, 26976419, 31422574, 36315919).All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798310	SCV002041960	uncertain significance	Breast and/or ovarian cancer	2023-05-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115151	SCV002529820	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-24	criteria provided, single submitter	curation
Athena Diagnostics	RCV000589762	SCV002771660	uncertain significance	not provided	2022-05-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589762	SCV004133248	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	ATM: PM2, BP4
Baylor Genetics	RCV003460800	SCV004206322	uncertain significance	Familial cancer of breast	2024-02-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003460800	SCV005083879	likely benign	Familial cancer of breast	2024-05-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589762	SCV001550722	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATM p.Ser759Gly variant was identified in 3 of 1550 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer (Caminsky 2016, Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs148705269) as "With Uncertain significance allele", ClinVar (6x uncertain significance), and Clinvitae (3x uncertain significance). The variant was not identified in COGR, Cosmic, MutDB, LOVD 3.0, or ATM-LOVD. The variant was identified in control databases in 8 of 276952 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the European population in 8 of 126678 chromosomes (freq: 0.00006), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser759 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000205470	SCV002079628	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-20	no assertion criteria provided	clinical testing