Submissions for variant NM_000051.4(ATM):c.496+4T>C

gnomAD frequency: 0.00007  dbSNP: rs587781375

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129193	SCV000183932	likely benign	Hereditary cancer-predisposing syndrome	2019-02-05	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.
GeneDx	RCV000211949	SCV000209584	benign	not specified	2014-06-23	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.
Invitae	RCV000474202	SCV000546724	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585055	SCV000692729	uncertain significance	not provided	2017-07-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000474202	SCV000799740	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000474202	SCV000838471	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129193	SCV000902853	likely benign	Hereditary cancer-predisposing syndrome	2016-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211949	SCV000916580	uncertain significance	not specified	2024-02-05	criteria provided, single submitter	clinical testing	Variant summary: ATM c.496+4T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation 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 8.8e-05 in 251312 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (8.8e-05 vs 0.001), allowing no conclusion about variant significance. c.496+4T>C has been reported in the literature in individuals affected with Breast Cancer (Jalkh_2017, Mitchell_2018), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with disease. The variant was also reported in 2/7325 European American women, who were older than age 70, and have never had cancer (FLOSSIES database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28202063, 29659587, 25980754). ClinVar contains an entry for this variant (Variation ID: 140926). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Baylor Genetics	RCV000474202	SCV001520233	uncertain significance	Ataxia-telangiectasia syndrome	2020-06-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000129193	SCV001911465	likely benign	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The intronic c.496+4T>C variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer (BP4). Splicing analysis in carrier RNA with proper design and controls showed only the wild-type transcript although do not demonstrate biallelic expression by an exonic SNV (BS3_Supporting; O.Díez, unpublished data). This variant has an allele frequency of 0.000082 (0.008%, 22/268,180 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00019 (0.02%, 22/118,056 alleles) in the European (non-Finnish) subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BP4 + BS3_Supporting (PMID: 33280026).
Genetic Services Laboratory, University of Chicago	RCV000211949	SCV002067637	uncertain significance	not specified	2018-11-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129193	SCV002527712	likely benign	Hereditary cancer-predisposing syndrome	2021-07-13	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585055	SCV004221131	uncertain significance	not provided	2023-09-14	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 28202063 (2017), 28779002 (2017), 29659587 (2018)) and colorectal cancer (PMID: 33280026 (2021)). Additionally, this variant has been observed in elderly cancer free women (Flossies, (https://whi.color.com/)). The frequency of this variant in the general population, 0.00018 (23/129072 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect ATM mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.
PreventionGenetics, part of Exact Sciences	RCV004551241	SCV004736435	likely benign	ATM-related disorder	2023-07-31	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000129193	SCV005045378	likely benign	Hereditary cancer-predisposing syndrome	2024-04-16	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000129193	SCV000787868	uncertain significance	Hereditary cancer-predisposing syndrome	2017-09-21	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357828	SCV001553415	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM c.496+4T>C variant was identified in 4 of 2610 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and Lynch Syndrome (Jalkh 2017,Yurgelun 2015, ). The variant was identified in dbSNP (rs587781375) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Counsyl, Integrated Genetics and 4 other submitters, benign by GeneDx and likely benign by Color). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 23 of 282,719 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 23 of 129,072 chromosomes (freq: 0.0002), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. The variant was reported in an individual with a co-occurring pathogenic STK11 variant (c.375-1C>T) (Jalkh 2017). The c.496+4T>C variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 4 out of 4 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.