Submissions for variant NM_000051.4(ATM):c.6315G>C (p.Arg2105Ser)

gnomAD frequency: 0.00006  dbSNP: rs587780632

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122871	SCV000166129	benign	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131258	SCV000186222	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-19	criteria provided, single submitter	clinical testing	The p.R2105S variant (also known as c.6315G>C), located in coding exon 42 of the ATM gene, results from a G to C substitution at nucleotide position 6315. The arginine at codon 2105 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified in a 65-year-old woman with idiopathic retinal telangiectasia (Mauget-Faysse M et al. Invest. Ophthalmol. Vis. Sci. 2003 Aug;44:3257-62). In addition, this alteration was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). Another missense alteration at this position, p.R2105T (c.6314G>C), has been reported in a small cohort of Spanish early-onset breast cancer patients (Brunet J et al. Clin. Genet. 2008 May;73:465-73). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000589612	SCV000292472	uncertain significance	not provided	2024-10-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with idiopathic ocular telangiectasias as well as in individuals with personal or family history of breast, pancreatic or other cancers (PMID: 12882767, 25186627, 25980754, 33280026, 33436325, 33939675, 35534704, 33471991); This variant is associated with the following publications: (PMID: 25980754, 25186627, 12882767, 33436325, 33280026, 33471991, 33939675, 31206626, 36315919, 35451682, 35534704, 36845387, 23532176)
Color Diagnostics, LLC DBA Color Health	RCV000131258	SCV000537592	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 2105 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on 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 idiopathic ocular telangiectasia (PMID: 12882767), breast cancer (PMID: 25186627), and Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). In a large international case-control study, this variant was reported in 1/60465 breast cancer cases and absent in 53461 controls (PMID: 33471991). This variant has also been identified in 26/251292 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	RCV001293417	SCV000694320	uncertain significance	not specified	2023-06-26	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6315G>C (p.Arg2105Ser) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) of 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 0.0001 in 251292 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.004), allowing no conclusion about variant significance. c.6315G>C has been reported in the literature in individuals affected with idiopathic retinal telangiectasia (e.g., Mauget-Faysse_2003), breast cancer (e.g., Tung_2015, Feliubadalo_2020), chronic lymphocytic leukemia (Lampson_2023), prostate cancer (Karlsson_2021), and Lynch syndrome-associated cancer and/or polyps (e.g., Yurgelun_2015) as well an individual with a family history of pancreatic cancer (Zhu_2021), however without strong evidence for causality in all cases (e.g., lack of co-segregation and co-occurrence data). The variant was also found in controls (example, Weitzel_2019). These reports therefore 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: 33280026, 12882767, 25186627, 31206626, 25980754, 33436325, 36315919, 33939675). Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=8) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000122871	SCV001138536	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000131258	SCV001911476	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.6315G>C (p.Arg2105Ser) variant has an allele frequency of 0.00011 (0.01%, 26/236,754 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00032 (0.03%, 11/34,260 alleles) in the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice – GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PP3 (PMID: 33280026).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589612	SCV002010795	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001293417	SCV002066667	uncertain significance	not specified	2020-11-23	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.6315G>C, in exon 43 that results in an amino acid change, p.Arg2105Ser. This sequence change has been described in the gnomAD database with a frequency of 0.14% in the Ashkenazi Jewish sub-population (dbSNP rs587780632). The p.Arg2105Ser change has been previously reported in an individual with idiopathic ocular telangiectasia (PMID: 12882767). Additionally, a different sequence change at the same location, p.Arg2105Thr, has been reported in an individual with breast cancer (PMID: 18384426). The p.Arg2105Ser change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Arg2105Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg2105Ser change remains unknown at this time.
Sema4, Sema4	RCV000131258	SCV002537233	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-24	criteria provided, single submitter	curation
Baylor Genetics	RCV003467085	SCV004207044	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356310	SCV001551441	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Arg2105Ser variant was identified in 2 of 2580 proband chromosomes (frequency: 0.00078) from individuals or families with Lynch syndrome and ocular telangiectasia and was not identified in 156 control chromosomes from healthy individuals (Mauget-Faysse 2003, Yurgelun 2015). The variant was also identified in the following databases: dbSNP (ID: rs587780632) as “With Uncertain significance allele”, ClinVar (as uncertain significance by Invitae, Ambry Genetics, GeneDx, and Color Genomics), and Clinvitae (3x as uncertain significance). The variant was not identified in Cosmic, MutDB, and LOVD 3.0 databases. The variant was identified in control databases in 24 of 246108 chromosomes at a frequency of 0.000098 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 2 of 5480 chromosomes (freq: 0.000365), Latino in 11 of 33580 chromosomes (freq: 0.000328), and Ashkenazi Jewish in 11 of 9842 chromosomes (freq: 0.001118); the variant was not observed in the African, European (Non-Finnish), East Asian, European (Finnish), and South Asian populations. The p.Arg2105Ser residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004551200	SCV004104463	uncertain significance	ATM-related disorder	2024-02-22	no assertion criteria provided	clinical testing	The ATM c.6315G>C variant is predicted to result in the amino acid substitution p.Arg2105Ser. This variant was seen in an individual undergoing Lynch syndrome testing (Yurgelun et al. 2015. PubMed ID: 25980754) and an individual with idiopathic juxtafoveolar retinal telangiectasia (Mauget-Faÿsse et al. 2003. PubMed ID: 12882767). This variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant was determined to be of uncertain clinical significance by a large consortium evaluating predisposition to prostate cancer (Karlsson et al. 2021. PubMed ID: 33436325), and it has conflicting interpretations in ClinVar, ranging from benign to uncertain clinical significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/135767/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.