Submissions for variant NM_000051.4(ATM):c.6795C>T (p.Phe2265=)

gnomAD frequency: 0.00038  dbSNP: rs3218699

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122878	SCV000166136	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000212049	SCV000167053	benign	not specified	2014-01-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000123710	SCV000212931	likely benign	Hereditary cancer-predisposing syndrome	2014-07-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV000122878	SCV000367065	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.
Color Diagnostics, LLC DBA Color Health	RCV000123710	SCV000537473	likely benign	Hereditary cancer-predisposing syndrome	2015-04-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212049	SCV000593489	likely benign	not specified	2017-04-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679140	SCV000805608	likely benign	not provided	2017-01-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212049	SCV000916583	likely benign	not specified	2018-06-18	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6795C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 273300 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.6795C>T, has been reported in the literature with limited information (Bernstein_2010, Pettitt_2001). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (3x) and uncertain signifncance (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Athena Diagnostics	RCV000679140	SCV001143120	likely benign	not provided	2019-07-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679140	SCV001473567	likely benign	not provided	2020-04-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000123710	SCV002538461	likely benign	Hereditary cancer-predisposing syndrome	2021-05-18	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149833	SCV003837884	likely benign	Breast and/or ovarian cancer	2021-07-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679140	SCV004133268	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	ATM: BP4, BP7
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679140	SCV004222059	likely benign	not provided	2022-03-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589608	SCV005084804	benign	Familial cancer of breast	2024-06-10	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Natera, Inc.	RCV000122878	SCV001466202	likely benign	Ataxia-telangiectasia syndrome	2020-04-03	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356930	SCV001552225	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Phe2265= variant was identified in 11 of 30,384 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer and was present in 8 of 10,976 control chromosomes (frequency: 0.0007) from healthy individuals (Bernstein 2010, Decker 2017). The variant was identified in dbSNP (rs3218699) as “with uncertain significance, other allele” and ClinVar (classified as likely benign by Color, Ambry Genetics, Invitae and 3 other submitters, benign by GeneDx and uncertain significance by Illumina). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 57 of 278,902 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 49 of 128,014 chromosomes (freq: 0.0004), Other in 2 of 7164 chromosomes (freq: 0.0003), Latino in 3 of 35,362 chromosomes (freq: 0.00009), African in 2 of 24,802 chromosomes (freq: 0.00008), Finnish in 1 of 22,828 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The p.Phe2265= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.