Submissions for variant NM_000051.4(ATM):c.37C>T (p.Arg13Cys)

gnomAD frequency: 0.00001  dbSNP: rs141586345

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165494	SCV000216225	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-14	criteria provided, single submitter	clinical testing	The p.R13C variant (also known as c.37C>T), located in coding exon 1 of the ATM gene, results from a C to T substitution at nucleotide position 37. The arginine at codon 13 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple breast cancer cohorts, as well as, in controls (Broeks A et al. Breast Cancer Res Treat. 2008 Jan;107(2):243-8; Momozawa Y et al. Nat Commun. 2018 10;9:4083; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094). This alteration has also been reported with a carrier frequency of 0.00065 in 7,636 unselected prostate cancer patients and 0.00008 in 12,366 male controls of Japanese ancestry (Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376). Additionally, this alteration was reported in a cohort of patients diagnosed with pancreatic ductal adenocarcinoma (Ohmoto A et al. J Gastroenterol. 2018 Oct;53:1159-1167). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230359	SCV000282942	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 13 of the ATM protein (p.Arg13Cys). This variant is present in population databases (rs141586345, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 10677309, 17393301, 19781682). ClinVar contains an entry for this variant (Variation ID: 185977). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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.
GeneDx	RCV000589373	SCV000293426	uncertain significance	not provided	2018-01-30	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.37C>T at the cDNA level, p.Arg13Cys (R13C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been observed in at least two women with breast cancer (Broeks 2000, Broeks 2008, Tavtigian 2009). ATM Arg13Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg13Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260254	SCV000694265	uncertain significance	not specified	2020-09-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.37C>T (p.Arg13Cys) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) 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 2.6e-05 in 303338 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.37C>T has been reported in the literature in individuals affected with breast cancer, pancreatic ductal adenocarcinoma and chronic lymphocytic leukemia (Ohmoto_2018, te Raa_2015, Tavtigian_2009, Broeks_2008). These reports however, 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. Five other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000230359	SCV000792114	uncertain significance	Ataxia-telangiectasia syndrome	2017-06-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165494	SCV000911423	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 13 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. The variant has been observed in individuals affected with breast cancer (PMID: 17393301, 19781682, 33471991), in an individual with personal or family history of pancreatic cancer (PMID: 29667044), and in multiple unaffected individuals (PMID: 30287823, 33471991). This variant has been identified in 5/251386 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.
Baylor Genetics	RCV003462175	SCV004207752	uncertain significance	Familial cancer of breast	2023-08-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000230359	SCV002090143	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-28	no assertion criteria provided	clinical testing