Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000164443 | SCV000215083 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-14 | criteria provided, single submitter | clinical testing | The p.T935R variant (also known as c.2804C>G), located in coding exon 17 of the ATM gene, results from a C to G substitution at nucleotide position 2804. The threonine at codon 935 is replaced by arginine, an amino acid with similar properties. This variant has been detected in a Brazilian individual with sporadic breast cancer and loss-of-heterozygosity observed in her tumor (Mangone FR et al. Springerplus. 2015 Jan;4:23). This alteration was identified in a cohort of patients diagnosed with biliary tract carcinoma undergoing multigene panel testing for hereditary cancer risk (Terashima T et al. Oncotarget. 2019 Oct;10:5949-5957). This alteration was observed in with an allele frequency of 0.00979 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.01005 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 0.0091 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This variant has also been identified in 99/12403 unselected Japanese colorectal cancer patients and in 226/23478 controls (Fujita M et al. Clin Gastroenterol Hepatol, 2022 Sep;20:2132-2141.e9). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Labcorp Genetics |
RCV000557491 | SCV000622362 | uncertain significance | Ataxia-telangiectasia syndrome | 2024-01-25 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 935 of the ATM protein (p.Thr935Arg). This variant is present in population databases (rs3218708, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer, biliary tract cancer, uterus cancer (PMID: 25625042, 34326862, 36243179). ClinVar contains an entry for this variant (Variation ID: 185083). 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. |
Counsyl | RCV000557491 | SCV000800472 | uncertain significance | Ataxia-telangiectasia syndrome | 2018-06-07 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000164443 | SCV000903257 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-11-16 | criteria provided, single submitter | clinical testing | This missense variant replaces threonine with arginine at codon 935 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: 25625042, 33471991). In a Japanese colorectal cancer risk case-control study, this variant was reported in 99/12502 colorectal cancer cases and 226/23704 controls (PMID: 33309985). This variant has been identified in 5/251396 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, |
RCV000779788 | SCV000916590 | likely benign | not specified | 2023-02-13 | criteria provided, single submitter | clinical testing | Variant summary: ATM c.2804C>G (p.Thr935Arg) results in a non-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 0.00077 in 298352 control chromosomes, predominantly at a frequency of 0.00027 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the gnomAD database are insufficient to allow any conclusion about variant significance. c.2804C>G has been reported in the literature predominantly in reports of East Asian/Japanese cohorts of unaffected controls and in ethnicity-matched individuals affected with breast/colorectal cancer and/or with a personal/family history of cancer (example, Jiang_2018, Mangone_2015, Fujita_2020, Terashima_2019, Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. At least one recent report classifies this variant as benign based on a high frequency in Japanese population (Fujita_2020). It has also been reported at an allele frequency of 0.0061 in the Japanese Whole Genome Reference Panel (ToMMo 38KJPN) dataset of 38,000 Japanese individuals, including 7 homozygotes, strongly suggesting it is a benign polymorphism found primarily in individuals of East Asian/Japanese ancestry. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and one Japanese research foundation have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=6) or likely benign (n=1). Some submitters cite overlapping but not all evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. |
Cancer Genomics Group, |
RCV001030525 | SCV001193473 | likely benign | Hereditary breast ovarian cancer syndrome | 2019-05-01 | criteria provided, single submitter | research | |
Illumina Laboratory Services, |
RCV000557491 | SCV001263806 | uncertain significance | Ataxia-telangiectasia syndrome | 2017-04-28 | criteria provided, single submitter | clinical testing | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. |
Gene |
RCV003238729 | SCV003936415 | uncertain significance | not provided | 2023-02-22 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or colorectal cancer as well as unaffected controls (Mangone et al., 2015; Momozawa et al., 2018; Fujita et al., 2020); This variant is associated with the following publications: (PMID: 25625042, 29642553, 33309985, 30287823, 31666926) |
Natera, |
RCV000557491 | SCV001452053 | uncertain significance | Ataxia-telangiectasia syndrome | 2020-09-16 | no assertion criteria provided | clinical testing |