Submissions for variant NM_000051.4(ATM):c.2771G>A (p.Arg924Gln)

gnomAD frequency: 0.00008  dbSNP: rs587782298

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131181	SCV000186128	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	The p.R924Q variant (also known as c.2771G>A), located in coding exon 17 of the ATM gene, results from a G to A substitution at nucleotide position 2771. The arginine at codon 924 is replaced by glutamine, an amino acid with highly similar properties. This alteration was observed with an allele frequency of 0.00113 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00089 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0011 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). In a study of 196 women with breast cancer and 185 unaffected controls from Cameroon and Uganda, this variant was observed in a breast cancer patient from Uganda (Adedokun B et al. Cancer Epidemiol. Biomarkers Prev. 2020 02;29:359-367). This alteration has also been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J. Hum. Genet. 2009 Oct;85(4):427-46) and in 1/29 ovarian cancer patients in a Japanese cohort (Tomioka K el al. Sci Rep 2021 10;11(1):19661). This amino acid position is highly 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	RCV000465123	SCV000547012	uncertain significance	Ataxia-telangiectasia syndrome	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 924 of the ATM protein (p.Arg924Gln). This variant is present in population databases (rs587782298, gnomAD 0.04%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 19781682, 30287823, 31871109, 32068069). ClinVar contains an entry for this variant (Variation ID: 142194). 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.
GeneDx	RCV000483446	SCV000564621	uncertain significance	not provided	2022-06-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 26314984, 27105424, 30287823, 31871109)
Color Diagnostics, LLC DBA Color Health	RCV000131181	SCV000682076	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 924 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: 19781682, 30287823, 31871109, 32068069, 33471991) and in unaffected individuals (PMID: 30287823, 33471991). This variant has been identified in 19/251440 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030524	SCV001193472	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193037	SCV001361582	uncertain significance	not specified	2024-02-26	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2771G>A (p.Arg924Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 303700 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00014 vs 0.001), allowing no conclusion about variant significance. c.2771G>A has been reported in the literature in individuals affected with Breast Cancer (e.g., Tavtigian_2009, Momozawa_2018, Adedokun_2020, Kwong_2020). These reports 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: 19781682, 30287823, 31871109, 32068069, 36243179). ClinVar contains an entry for this variant (Variation ID: 142194). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002492511	SCV002789970	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-01-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467166	SCV004209556	uncertain significance	Familial cancer of breast	2023-08-24	criteria provided, single submitter	clinical testing
Department of Pediatrics, Samsung Medical Center, Samsung Medical Center	RCV001252852	SCV001163995	uncertain significance	Microcephaly		no assertion criteria provided	research
Natera, Inc.	RCV000465123	SCV002084153	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739451	SCV005356130	uncertain significance	ATM-related disorder	2024-04-27	no assertion criteria provided	clinical testing	The ATM c.2771G>A variant is predicted to result in the amino acid substitution p.Arg924Gln. This variant was reported in individuals with breast/biliary tract cancer (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table SD1, Momozawa et al. 2018. PubMed ID: 30287823; Tbale S1, Adedokun et al. 2019. PubMed ID: 31871109; Table S2, Okawa et al. 2022. PubMed ID: 36243179). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD. In ClinVar, this variant is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142194/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.