Submissions for variant NM_000051.4(ATM):c.5009C>T (p.Ala1670Val)

gnomAD frequency: 0.00002  dbSNP: rs375131360

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115202	SCV000149111	uncertain significance	not provided	2023-03-01	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; Published functional studies suggest no impact on splicing (Casadei et al., 2019); This variant is associated with the following publications: (PMID: 31422574, 27720647, 28652578, 34173971, 31843900, 20305132)
Invitae	RCV000206394	SCV000261480	uncertain significance	Ataxia-telangiectasia syndrome	2024-02-01	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 1670 of the ATM protein (p.Ala1670Val). This variant is present in population databases (rs375131360, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 20305132). ClinVar contains an entry for this variant (Variation ID: 127397). 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 disruptive. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (PMID: 31843900; 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	RCV000561604	SCV000660480	likely benign	Hereditary cancer-predisposing syndrome	2022-01-18	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.
Color Diagnostics, LLC DBA Color Health	RCV000561604	SCV000682242	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 1670 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 20305132, 33471991), as well as in healthy individuals (PMID: 28652578, 33471991). This variant has been identified in 3/282458 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.
Athena Diagnostics	RCV000115202	SCV002771709	uncertain significance	not provided	2021-06-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490773	SCV002789643	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-04-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001171473	SCV003800794	uncertain significance	not specified	2024-01-08	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5009C>T (p.Ala1670Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251062 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5009C>T has been reported in the literature in at least one individual affected with Breast Cancer (e.g. Bernstein_2010, Casadei_2019). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 20305132, 31843900). ClinVar contains an entry for this variant (Variation ID: 127397). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV003315637	SCV004019684	likely benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
King Laboratory, University of Washington	RCV001171473	SCV001251387	benign	not specified	2019-09-01	no assertion criteria provided	research
Natera, Inc.	RCV000206394	SCV002078384	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-29	no assertion criteria provided	clinical testing