Submissions for variant NM_000051.4(ATM):c.2449G>C (p.Asp817His)

gnomAD frequency: 0.00003  dbSNP: rs587778067

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656758	SCV000209703	uncertain significance	not provided	2024-03-12	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 breast and other cancers as well as unaffected controls (PMID: 25186627, 27443514, 31206626); This variant is associated with the following publications: (PMID: 24728327, 25186627, 31206626, 27443514, 32134843)
Ambry Genetics	RCV000159695	SCV000218248	likely benign	Hereditary cancer-predisposing syndrome	2021-05-14	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168026	SCV000218678	likely benign	Ataxia-telangiectasia syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159695	SCV000292218	likely benign	Hereditary cancer-predisposing syndrome	2021-08-25	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV001250428	SCV001424789	uncertain significance	Familial cancer of breast	2019-09-10	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in an individual with endometrial cancer and an individual with breast cancer (Tung 2015, Ring 2016). This variant has a combined allele frequency of 0.0003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/) and is more common in individuals of Latinx ancestry (Lek 2016). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.
Baylor Genetics	RCV000168026	SCV001481660	uncertain significance	Ataxia-telangiectasia syndrome	2020-06-16	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120124	SCV001623174	uncertain significance	not specified	2024-08-16	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2449G>C (p.Asp817His) results in a non-conservative amino acid change in 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 0.00029 in 251016 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00029 vs 0.004), allowing no conclusion about variant significance. c.2449G>C has been reported in the literature in individuals affected breast cancer (e.g. Tung_2014, Weitzel_2019) and endometrial cancer (e.g. Ring_2016), but also in healthy controls and in a healthy individual screened by whole-genome sequencing (e.g. Weitzel_2019, Bodian_2014). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. 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: 24728327, 25186627, 27443514, 31206626). ClinVar contains an entry for this variant (Variation ID: 133608). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000168026	SCV001781322	uncertain significance	Ataxia-telangiectasia syndrome	2021-07-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000159695	SCV002532155	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-04	criteria provided, single submitter	curation
ITMI	RCV000120124	SCV000084262	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000168026	SCV001462070	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356154	SCV001551236	uncertain significance	Endometrial carcinoma		no assertion criteria provided	clinical testing	The ATM p.Asp817His variant was identified in 2 of 5078 proband chromosomes (frequency: 0.0004) from individuals with endometrial and breast cancer and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Ring 2016, Tung 2015, Bodian 2014). The variant was identified in dbSNP (rs587778067) as “with uncertain significance allele”, ClinVar (interpreted as "uncertain significance" by Invitae and 3 others). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 69 of 245,874 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 5480 chromosomes (freq: 0.0004), Latino in 66 of 33,570 chromosomes (freq: 0.002), and South Asian in 1 of 30,760 chromosomes (freq: 0.00003). The variant was not observed in the African, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asp817 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004551177	SCV004718581	likely benign	ATM-related disorder	2024-02-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).