Submissions for variant NM_000051.4(ATM):c.6257A>T (p.Tyr2086Phe)

gnomAD frequency: 0.00001  dbSNP: rs730881380

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159745	SCV000209760	uncertain significance	not provided	2020-03-05	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with breast cancer (Hauke 2018); This variant is associated with the following publications: (PMID: 29522266)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231734	SCV000283011	uncertain significance	Ataxia-telangiectasia syndrome	2022-09-20	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 2086 of the ATM protein (p.Tyr2086Phe). This variant is present in population databases (rs730881380, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer and/or prostate cancer (PMID: 29522266, 33436325). ClinVar contains an entry for this variant (Variation ID: 181977). 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.
Ambry Genetics	RCV000568069	SCV000665456	likely benign	Hereditary cancer-predisposing syndrome	2024-03-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000568069	SCV000682319	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-03	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with phenylalanine at codon 2086 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251412 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	RCV001731490	SCV001983533	uncertain significance	not specified	2023-11-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6257A>T (p.Tyr2086Phe) results in a conservative amino acid change located in the PIK-related kinase domain (IPR014009) of 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 1.6e-05 in 365040 control chromosomes (gnomAD, Dorling_2021, Karlsson_2021). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6257A>T has been reported in the literature in individuals with a personal or family history of cancer (e.g., Hauke_2018, Dorling_2021, Bhai_2021, deOliveira-Garcia_2022), but it was also reported in unaffected controls (e.g., Dorling_2021, Karlsson_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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: 33471991, 29522266, 33436325, 34326862, 35181726). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
MGZ Medical Genetics Center	RCV002288674	SCV002580173	uncertain significance	Familial cancer of breast	2022-08-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002288674	SCV004203860	uncertain significance	Familial cancer of breast	2023-11-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000231734	SCV001457412	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV002288674	SCV004099445	uncertain significance	Familial cancer of breast	2023-10-30	no assertion criteria provided	clinical testing