Submissions for variant NM_000051.4(ATM):c.7316T>C (p.Val2439Ala)

gnomAD frequency: 0.00001  dbSNP: rs776266049

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164769	SCV000215445	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	The p.V2439A variant (also known as c.7316T>C), located in coding exon 49 of the ATM gene, results from a T to C substitution at nucleotide position 7316. The valine at codon 2439 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in 2/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian SV et al. Am J Hum Genet. 2009 Oct; 85(4):427-46). This alteration was also identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352) as well as in 1/104 cases of familial cancer patients in an Italian cohort (Paduano F et al. Genes (Basel) 2022 Jul;13(7)). This amino acid position is not well 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.
GeneDx	RCV000590493	SCV000617374	uncertain significance	not provided	2022-08-08	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; Identified in patients with prostate, breast, and/or ovarian cancer, including one individual who also carried a pathogenic BRCA2 variant (Thorstenson et al., 2003; Tavtigian et al., 2009; Akcay et al., 2020; Bandeira et al., 2021; Paduano et al., 2022); This variant is associated with the following publications: (PMID: 19781682, 12810666, 24970356, 26193622, 32986223, 32658311, 23532176, 35886069)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543915	SCV000622734	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2439 of the ATM protein (p.Val2439Ala). This variant is present in population databases (rs776266049, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 12810666, 19781682, 32658311, 32986223, 35886069). ClinVar contains an entry for this variant (Variation ID: 185361). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000164769	SCV000682403	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 2439 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 cancer and ovarian cancer (PMID: 12810666, 19781682, 32658311, 32986223). This variant has been identified in 2/282380 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328041	SCV000694349	uncertain significance	not specified	2021-03-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7316T>C (p.Val2439Ala) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.9e-06 in 256756 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7316T>C has been reported in the literature in individuals affected with Breast Cancer (Thorstenson_2003, Akcay_2020, Bandeira_2020) as well as one individual with severe short stature of unknown etiology (Guo_2014). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One co-occurrence with another pathogenic variant has been reported (BRCA2 c.5909C>A, p.Ser1970X, Bandeira_2020), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000543915	SCV001138561	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468722	SCV004209476	uncertain significance	Familial cancer of breast	2024-01-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000543915	SCV002080555	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-20	no assertion criteria provided	clinical testing