Submissions for variant NM_000051.4(ATM):c.6974C>T (p.Ala2325Val)

gnomAD frequency: 0.00001  dbSNP: rs200940211

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212052	SCV000149145	uncertain significance	not provided	2024-02-11	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 breast cancer and in at least one individual with a Lynch-syndrome associated cancer and/or polyps (PMID: 26689913, 25186627, 25980754, 32068069); This variant is associated with the following publications: (PMID: 25980754, 24651015, 25186627, 28652578, 32068069, 23532176, 26689913)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122881	SCV000166139	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2325 of the ATM protein (p.Ala2325Val). This variant is present in population databases (rs200940211, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and with clinical features of Lynch syndrome (PMID: 25186627, 25980754, 32068069). ClinVar contains an entry for this variant (Variation ID: 127431). 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.
Ambry Genetics	RCV000115236	SCV000218222	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-23	criteria provided, single submitter	clinical testing	The p.A2325V variant (also known as c.6974C>T), located in coding exon 46 of the ATM gene, results from a C to T substitution at nucleotide position 6974. The alanine at codon 2325 is replaced by valine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000115236	SCV000682378	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 2325 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 25186627, 32068069) and in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). In a large international case-control study, this variant was reported in 8/60466 breast cancer cases and 7/53461 controls (OR=1.01, 95%CI 0.366 to 2.787; PMID: 33471991). This variant has been identified in 3/282678 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.
Mendelics	RCV000122881	SCV000838585	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001375520	SCV001572373	uncertain significance	not specified	2021-11-20	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6974C>T (p.Ala2325Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. 4/4 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 8e-06 in 251336 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6974C>T has been reported in the literature in individuals affected with breast Cancer/colorectal cancer in settings of multigene cancer panel testing (example, Kwong_2020, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002477275	SCV002794132	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-05-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460809	SCV004207606	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000115236	SCV000787879	uncertain significance	Hereditary cancer-predisposing syndrome	2018-02-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000122881	SCV001458457	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001375520	SCV003839225	uncertain significance	not specified	2022-06-13	no assertion criteria provided	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.6974C>T, in exon 47 that results in an amino acid change, p.Ala2325Val. This sequence change does not appear to have been previously described in individuals with ATM-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.0011% in the overall population (dbSNP rs200940211). The p.Ala2325Val change affects a poorly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Ala2325Val substitution appears to be benign/possibly benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ala2325Val change remains unknown at this time.