Submissions for variant NM_000051.4(ATM):c.8071C>T (p.Arg2691Cys)

gnomAD frequency: 0.00011  dbSNP: rs531980488

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131504	SCV000186493	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-11	criteria provided, single submitter	clinical testing	The p.R2691C variant (also known as c.8071C>T), located in coding exon 54 of the ATM gene, results from a C to T substitution at nucleotide position 8071. The arginine at codon 2691 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals diagnosed with breast cancer (Sommer SS et al. Cancer Genet Cytogenet, 2003 Sep;145:115-20; Heikkinen K et al. Int J Cancer, 2005 Aug;116:69-72; Bernstein JL et al. J Natl Cancer Inst, 2010 Apr;102:475-83; Xie Y et al. Clin Genet, 2018 Jan;93:41-51; Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367). It has also been reported in an individual with non-medullary thyroid cancer (Yu Y et al. Sci Rep, 2015 Nov;5:16129). This amino acid position is not 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.
Invitae	RCV000199628	SCV000254153	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2691 of the ATM protein (p.Arg2691Cys). This variant is present in population databases (rs531980488, gnomAD 0.06%). This missense change has been observed in individual(s) with breast cancer or prostate cancer (PMID: 12935922, 15756685, 19781682, 20305132, 26689913, 29522266, 31248605, 31871109). ClinVar contains an entry for this variant (Variation ID: 133636). 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 disruptive. 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	RCV000587628	SCV000568336	uncertain significance	not provided	2022-12-08	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 a personal history of breast or other cancers, but also identified in unaffected controls (Sommer et al., 2003; Heikkinen et al., 2005; Tavtigian et al., 2009; Guarini et al., 2012; Bodian et al., 2014; Yu et al., 2015; Yurgelun et al., 2017; Estiar and Mehdipour, 2018; Hauke et al., 2018; Xie et al., 2018); This variant is associated with the following publications: (PMID: 25563586, 24728327, 30197789, 29731985, 29134647, 12935922, 23633543, 28580595, 26530882, 19781682, 31871109, 15756685, 28135145, 21993670, 29522266, 29880898, 30311369, 33471991, 32107087, 32068069, 28652578, 20305132, 26689913, 31742824, 35406568, 31248605)
Color Diagnostics, LLC DBA Color Health	RCV000131504	SCV000682453	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 2691 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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: 12935922, 15756685, 19781682, 31871109, 33471991), colorectal cancer (PMID: 28135145), and thyroid cancer (PMID: 26530882). In a large international case-control study, this variant was reported in 13/60466 breast cancer cases and 9/53461 controls (OR=1.277, 95%CI 0.546 to 2.988, p-value=0.671; PMID: 33471991). In a separate meta-analysis of breast cancer case-control studies, this variant has shown inconclusive association with disease (PMID: 19781682). This variant has also been identified in 34/251216 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	RCV000120161	SCV000694370	uncertain significance	not specified	2023-03-17	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8071C>T (p.Arg2691Cys) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 258358 control chromosomes (gnomAD). 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.8071C>T has been reported in the literature in individuals affected with breast cancer, ovarian cancer, chronic lymphocytic leukemia, thyroid cancer, colorectal cancer, prostate cancer and lung cancer (Kwong_2020, Li_2020, Adedokun_2019, Wei_2019, Hauke_2018, Xie_2018, Yurgelun_2017, Lu_2015, Yu_2015, Guarini_2012, Bernstein_2010, Tavtigian_2009, Heikkinen_2005, Sommer_2003). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One co-occurrence with another pathogenic variant has been reported internally (PALB2 c.1451T>A, p.Leu484X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters have assessed the variant since 2014: all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000199628	SCV000791912	uncertain significance	Ataxia-telangiectasia syndrome	2017-06-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000199628	SCV000838606	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000199628	SCV001264108	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-27	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Division of Medical Genetics, University of Washington	RCV001250430	SCV001424795	uncertain significance	Familial cancer of breast	2019-08-30	criteria provided, single submitter	clinical testing	The c.8071C>T variant has been reported in individuals with breast cancer [PMID: 12935922, 20305132, 19781682 ] and also in individuals with no history of cancer [PMID: 24728327, 19781682]. The c.8071C>T variant has an allele frequency of 0.0001353 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect; however, there are no functional studies to verify or refute these predictions. At this time, it is unknown at this time whether or not this variant increases cancer risk; therefore, we interpret it as a variant of uncertain significance.
Sema4, Sema4	RCV000131504	SCV002537834	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-13	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492419	SCV002784428	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-09-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001250430	SCV004210111	uncertain significance	Familial cancer of breast	2023-07-29	criteria provided, single submitter	clinical testing
ITMI	RCV000120161	SCV000084303	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000199628	SCV001462598	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153382	SCV003843789	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing