Submissions for variant NM_000051.4(ATM):c.8072G>A (p.Arg2691His)

gnomAD frequency: 0.00001  dbSNP: rs876658385

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218643	SCV000273525	likely benign	Hereditary cancer-predisposing syndrome	2023-11-30	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.
GeneDx	RCV000236137	SCV000293657	uncertain significance	not provided	2018-11-29	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.8072G>A at the cDNA level, p.Arg2691His (R2691H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. ATM Arg2691His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Arg2691His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628082	SCV000748972	uncertain significance	Ataxia-telangiectasia syndrome	2022-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2691 of the ATM protein (p.Arg2691His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with prostate cancer (PMID: 33436325). ClinVar contains an entry for this variant (Variation ID: 230098). 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.
Fulgent Genetics, Fulgent Genetics	RCV000764948	SCV000896120	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000218643	SCV001348049	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2691 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. In a large international case-control study, this variant was reported in 1/60465 breast cancer cases and 0/53461 controls (PMID: 33471991). This variant has been identified in 2/251206 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.
PreventionGenetics, part of Exact Sciences	RCV004547528	SCV004106698	uncertain significance	ATM-related disorder	2023-04-11	criteria provided, single submitter	clinical testing	The ATM c.8072G>A variant is predicted to result in the amino acid substitution p.Arg2691His. This variant was reported in an individual with prostate cancer (Table S4 - Karlsson et al. 2021. PubMed ID: 33436325). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108205757-G-A) and has been interpreted as uncertain in ClinVar (https://ncbi.nlm.nih.gov/clinvar/variation/230098/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV004567513	SCV005056913	uncertain significance	Familial cancer of breast	2024-03-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000628082	SCV002076874	uncertain significance	Ataxia-telangiectasia syndrome	2020-11-19	no assertion criteria provided	clinical testing