Submissions for variant NM_000051.4(ATM):c.2945G>A (p.Arg982His)

dbSNP: rs749471737

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164299	SCV000214929	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	The p.R982H variant (also known as c.2945G>A), located in coding exon 19 of the ATM gene, results from a G to A substitution at nucleotide position 2945. The arginine at codon 982 is replaced by histidine, an amino acid with highly similar properties. This alteration was detected in 3/224 unrelated Brazilian individuals with breast cancer (Sandoval RL et al. PLoS One, 2021 Feb;16:e0247363). It has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535) as well as in an individual diagnosed with colorectal cancer (Yurgelun MB et al. J Clin Oncol. 2017 Apr;35:1086-1095). 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	RCV000235707	SCV000293004	uncertain significance	not provided	2023-09-13	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; Observed in individuals with personal and/or family history of breast or other cancers (Mandelker et al., 2017; Yurgelun et al., 2017; Tsaousis et al., 2019; Bhai et al., 2021; Sandoval et al., 2021); This variant is associated with the following publications: (PMID: 28135145, 28873162, 28652578, 31159747, 19781682, 34326862, 33606809)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476746	SCV000546810	likely benign	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164299	SCV000682092	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 982 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, colorectal cancer or an unspecified cancer (PMID: 28135145, 28873162, 33606809). This variant has been identified in 2/251002 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.
Counsyl	RCV000476746	SCV000799718	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-02	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000164299	SCV000821844	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000476746	SCV001263809	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Mendelics	RCV002247564	SCV002516954	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164299	SCV002535223	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-29	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000164299	SCV004014941	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325192	SCV004031209	uncertain significance	Familial cancer of breast	2023-06-26	criteria provided, single submitter	clinical testing	The ATM c.2945G>A (p.Arg982His) missense change has a maximum subpopulation frequency of 0.0018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 33606809) and colorectal cancer (PMID: 28135145). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV003325192	SCV004210094	uncertain significance	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000476746	SCV002076514	uncertain significance	Ataxia-telangiectasia syndrome	2020-02-03	no assertion criteria provided	clinical testing