Submissions for variant NM_000051.4(ATM):c.6025T>C (p.Tyr2009His)

gnomAD frequency: 0.00001  dbSNP: rs199586999

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235107	SCV000209756	uncertain significance	not provided	2023-11-21	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast or prostate cancer, but also in healthy controls (PMID: 25186627, 28779002, 28652578, 34326862, 33471991, 33436325); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 25186627, 26238431, 28652578, 33436325, 33471991, 34326862, 23532176)
Ambry Genetics	RCV000159741	SCV000215334	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-14	criteria provided, single submitter	clinical testing	The p.Y2009H variant (also known as c.6025T>C), located in coding exon 40 of the ATM gene, results from a T to C substitution at nucleotide position 6025. The tyrosine at codon 2009 is replaced by histidine, 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 was also detected on a 25-gene panel test in a woman of Caucasian ancestry who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). 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	RCV000198834	SCV000254127	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 2009 of the ATM protein (p.Tyr2009His). This variant is present in population databases (rs199586999, gnomAD 0.003%). This missense change has been observed in individual(s) with ATM-related conditions (PMID: 25186627, 33436325, 34326862). ClinVar contains an entry for this variant (Variation ID: 181973). 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.
Color Diagnostics, LLC DBA Color Health	RCV000159741	SCV000682299	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-26	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 2009 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 but also in unaffected controls (PMID: 25186627, 28652578, 28779002, 33471991). This variant has been identified in 4/282688 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.
Illumina Laboratory Services, Illumina	RCV000198834	SCV001263991	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-12	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731407	SCV001983478	uncertain significance	not specified	2024-04-29	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6025T>C (p.Tyr2009His) results in a conservative amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 253324 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6025T>C has been reported in the literature in settings of multigene panel testing in individuals affected with breast cancer or prostate cancer as well as in healthy controls (Tung_2014, Tiao_2017, Karlsson_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia and/or AT-related Breast/Prostate been reported. 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: 33436325, 26238431, 28652578, 25186627). ClinVar contains an entry for this variant (Variation ID: 181973). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000159741	SCV002537550	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
Baylor Genetics	RCV003467235	SCV004210330	uncertain significance	Familial cancer of breast	2024-02-16	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000198834	SCV002077997	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-26	no assertion criteria provided	clinical testing