Submissions for variant NM_000051.4(ATM):c.6988C>G (p.Leu2330Val)

gnomAD frequency: 0.00075  dbSNP: rs148432863

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587802	SCV000149147	likely benign	not provided	2021-05-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19781682, 12810666, 25980754, 11505391, 23555315)
Invitae	RCV000122882	SCV000166140	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115238	SCV000172962	likely benign	Hereditary cancer-predisposing syndrome	2020-09-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212054	SCV000694339	benign	not specified	2020-09-25	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6988C>G (p.Leu2330Val) results in a conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of 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 0.00021 in 250962 control chromosomes, predominantly at a frequency of 0.0026 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.6-fold of the estimated maximal expected allele frequency for a pathogenic variant (MPAF) in ATM causing Breast Cancer phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. In addition, the variant was reported in 17/ 2559 African American women (i.e. with an allele frequency of 0.0033), who were older than age 70, and have never had cancer (in the FLOSSIES database); this allele frequency is 3.3-fold higher than the MPAF (0.001), strongly suggesting that the variant is benign. c.6988C>G has been reported in the literature in individuals affected with breast cancer (Teraoka_2001, Tavtigian_2009, Bernstein_2010) and in one individual with Lynch syndrome-associated cancer and/or colorectal polyps (Yurgelun_2015), however without strong evidence for causality. Furthermore, no association with the disease was found for this variant in a large breast cancer case-control study (Haiman_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (2x) and likely benign (4x). Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV003492466	SCV000838587	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000587802	SCV000855439	uncertain significance	not provided	2017-07-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115238	SCV000902719	likely benign	Hereditary cancer-predisposing syndrome	2015-12-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000587802	SCV001502097	likely benign	not provided	2020-09-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212054	SCV002070979	likely benign	not specified	2021-05-26	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225325	SCV002504762	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115238	SCV002536820	likely benign	Hereditary cancer-predisposing syndrome	2020-07-07	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587802	SCV004222071	likely benign	not provided	2018-11-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925111	SCV004738454	likely benign	ATM-related condition	2022-07-06	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).
Natera, Inc.	RCV000122882	SCV001452130	uncertain significance	Ataxia-telangiectasia syndrome	2019-10-30	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587802	SCV001744647	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000587802	SCV001808702	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000587802	SCV001926301	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587802	SCV001980445	likely benign	not provided		no assertion criteria provided	clinical testing