Submissions for variant NM_000051.4(ATM):c.2260C>A (p.Gln754Lys)

gnomAD frequency: 0.00001  dbSNP: rs3205809

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130053	SCV000184880	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-15	criteria provided, single submitter	clinical testing	The p.Q754K variant (also known as c.2260C>A), located in coding exon 14 of the ATM gene, results from a C to A substitution at nucleotide position 2260. The glutamine at codon 754 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This alteration has been previously identified in an individual from a North American cohort of individuals with early onset colon cancer; however, this individual was also found to have a pathogenic mutation in the PMS2 gene (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). Computational analyses involving multiple in silico prediction models predict this alteration has uncertain potential for functional significance (George Priya Doss C et al. PLoS ONE, 2012 Apr;7:e34573). 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.
GeneDx	RCV000588063	SCV000209698	uncertain significance	not provided	2024-11-22	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer (PMID: 20305132, 27978560); Observed in an individual with colorectal cancer who had a pathogenic variant in PMS2 (PMID: 27978560); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22529920, 20305132, 28779002, 28652578, 28873162, 33471991, 35467778, 34326862, 27978560)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168206	SCV000218871	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 754 of the ATM protein (p.Gln754Lys). This variant is present in population databases (rs3205809, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 141496). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307402	SCV000694213	uncertain significance	not specified	2024-07-29	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2260C>A (p.Gln754Lys) 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 was absent in 250960 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.2260C>A has been reported in the literature in individuals affected with Breast, Colorectal, or Prostate Cancer (examples: Bernstein_2010, Pearlman_2017, Brady_2022). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with a pathogenic variant has been reported (PMS2 c.1831dup, p.Ile611AsnfsX2), providing supporting evidence for a benign role (Pearlman_2017). 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, 35467778, 27978560). ClinVar contains an entry for this variant (Variation ID: 141496). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000130053	SCV000913561	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with lysine at codon 754 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 (PMID: 28779002, 33471991) or prostate cancer (PMID: 35467778). This variant has been identified in 1/31402 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.
Sema4, Sema4	RCV000130053	SCV002536469	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-24	criteria provided, single submitter	curation
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000588063	SCV004026423	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	clinical testing	PM2_SUP
Baylor Genetics	RCV003474757	SCV004200747	uncertain significance	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000588063	SCV004226231	uncertain significance	not provided	2022-05-13	criteria provided, single submitter	clinical testing	PM2
PreventionGenetics, part of Exact Sciences	RCV004739438	SCV000805514	uncertain significance	ATM-related disorder	2024-09-26	no assertion criteria provided	clinical testing	The ATM c.2260C>A variant is predicted to result in the amino acid substitution p.Gln754Lys. This variant has been reported in a patient with colorectal cancer that also had a pathogenic variant in PMS2 (eTable 2 in Pearlman et al. 2017. PubMed ID: 27978560), and an individual in a study of ATM variants’ role in radiation-induced contralateral breast cancer in women (Supplementary Table 2 in Bernstein et al. 2010. PubMed ID: 20305132). This variant was identified in another individual with breast cancer in the UK (Decker B et al. 2017. PubMed ID: 28779002) and in an individual with prostate cancer (Brady L et al. 2022. PubMed ID: 35467778). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141496/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000588063	SCV001551512	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATM p.Gln754Lysvariant was identified in 1 of 900 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer (Pearlman 2017). The variant was identified in dbSNP (ID: rs3205809) as “With Uncertain significance allele”, and in ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx and two other submitters). The variant was identified in control databases in 1 of 30978 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017) in the European population in 1 of 15014 chromosomes (freq. 0.00006), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, South Asian or Finnish populations. The p.Gln754 residue is conserved in mammals however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Natera, Inc.	RCV000168206	SCV002079617	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-07	no assertion criteria provided	clinical testing