Submissions for variant NM_000051.4(ATM):c.4402G>A (p.Val1468Ile)

gnomAD frequency: 0.00034  dbSNP: rs369903995

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656760	SCV000149103	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal, prostate, breast, and thyroid cancer (Pearlman et al., 2017; Yehia et al., 2018; Giri et al., 2022); This variant is associated with the following publications: (PMID: 24728327, 28873162, 29684080, 36167400, 27978560, 35666082)
Ambry Genetics	RCV000115194	SCV000186529	likely benign	Hereditary cancer-predisposing syndrome	2022-10-27	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.
Eurofins Ntd Llc (ga)	RCV000656760	SCV000228684	uncertain significance	not provided	2015-05-08	criteria provided, single submitter	clinical testing
Invitae	RCV000199082	SCV000254107	likely benign	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000199082	SCV000838540	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115194	SCV000911162	likely benign	Hereditary cancer-predisposing syndrome	2015-11-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120138	SCV000918526	uncertain significance	not specified	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4402G>A (p.Val1468Ile) results in a 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 0.0001 in 270710 control chromosomes, predominantly at a frequency of 0.0008 within the African or African-American subpopulation in the gnomAD database. Another database, FLOSSIES, that contains unaffected individuals older than 70 years of age, observed the variant in 6/2559 African Americans, combining this data with the gnomAD occurrences could suggest the variant is a benign polymorphism found in populations of African origin. c.4402G>A has been reported in the literature in individuals affected with Prostate Cancer (Pearlman_2016, Giri_2022) including in one individual of African-American descent (Giri_2022). 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 ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple laboratories reported the variant with conflicting assessments including uncertain significance (n=7) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV001249853	SCV001424015	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-27	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>A) that results in a valine to isoleucine amino acid change at residue 1468 in the ATM protein. This is a previously reported, rare variant in control population datasets (gnomAD database, 28/276692 alleles, 0 homozygotes, 0.01% overall frequency) and has been observed in a single colon cancer patient (PMID 27978560), but no published breast cancer cases, to our knowledge. The Val1468 residue is not located in a domain known to be critical for ATM function, and studies adequately assessing the effect of this variant on protein function have not been identified. The Val1468 residue is highly evolutionarily conserved among mammalian species examined. Bioinformatic tools queried are in disagreement with whether this amino acid change would be damaging. There are multiple entries in ClinVar for this variant, all of which assert a clinical significance that is uncertain. Based upon the evidence, we are in agreement that the clinical significance of this variant is uncertain.
Baylor Genetics	RCV000199082	SCV001530023	uncertain significance	Ataxia-telangiectasia syndrome	2018-04-19	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000115194	SCV002534712	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-16	criteria provided, single submitter	curation
Baylor Genetics	RCV003467026	SCV004205823	uncertain significance	Familial cancer of breast	2023-10-30	criteria provided, single submitter	clinical testing
ITMI	RCV000120138	SCV000084278	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000199082	SCV001462324	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing